@article {pmid41510718,
year = {2026},
author = {Prabakaran, A and Sivaperuman, A and Natarajan, R and Nagarajan, NC and Solomon, VR},
title = {Innovative Approaches to Alzheimer's Treatment: Utilizing Tacrine Hybrids to Inhibit Amyloid Beta Aggregation as a Strategic Focus.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575422492251116190843},
pmid = {41510718},
issn = {1875-5607},
abstract = {Alzheimer's disease (AD) is a complex and progressive brain disorder marked by memory loss, cognitive decline, and behavioral changes. One of its defining features is the build-up of amyloid plaques, clumps of β-amyloid (Aβ) peptides, in the brain, along with the formation of neurofibrillary tangles. These Aβ peptides are generated when the amyloid precursor protein (APP) is cleaved by enzymes, with β-secretase (BACE1) playing a key role in the first step of this process. Because BACE1 starts the cascade that leads to harmful Aβ build-up, it has become an important target in the search for effective Alzheimer's treatments. As Aβ accumulates in neurons, it disrupts communication between brain cells and triggers oxidative stress, which worsens damage and accelerates disease progression. This is often exacerbated by imbalances in metal ions, such as copper and iron. While tacrine, an early acetylcholinesterase inhibitor, has shown benefits in managing AD symptoms, its limitations have led researchers to explore improved versions. One promising direction is the development of tacrine-based hybrid molecules. By combining tacrine with other chemical groups that have anti-β-amyloid (Aβ) effects, antioxidant properties, and metal-chelating properties, scientists aim to create compounds that target multiple aspects of the disease simultaneously. This review examines the emerging potential of tacrine hybrids, particularly their capacity to inhibit BACE1 and prevent Aβ aggregation, providing new hope for more effective and disease-modifying therapies for Alzheimer's disease.},
}

@article {pmid41510716,
year = {2026},
author = {Bano, A and Khan, AA and Kushwaha, SP and -, A and Zaidi, SMH and Misbahul Hasan, S and Fatima, A},
title = {Indole Scaffolds in Neurological Therapeutics: Synthesis, Structure-Activity Relationships and Drug-Receptor Interactions.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575415521251021091530},
pmid = {41510716},
issn = {1875-5607},
abstract = {INTRODUCTION: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.

METHODS: A detailed literature survey was conducted using databases such as Google Scholar, Elsevier, PubMed, ACS, PubChem, ScienceDirect, and RSC to understand the structural modifications of indole derivatives and their therapeutic potential. Both research and review articles related to indole- based compounds were thoroughly studied to prepare this review article.

RESULTS: There are over 40 FDA-approved drugs containing an indole nucleus used to treat various diseases, underscoring its potential in neurotherapeutics. This review highlights innovative synthetic strategies, including green chemistry approaches, that improve the drug-likeness and bioavailability of indole derivatives. Indole continues to be an indispensable scaffold in the development of novel therapeutics aimed at addressing the growing burden of neurological disorders.

DISCUSSION: This review aims to provide a comprehensive analysis of the therapeutic potential of indole-based compounds for the treatment of neurological disorders. However, challenges like blood-brain barrier permeability and long-term safety must be addressed for clinical success. Nonetheless, this review will help in designing and developing newer indole-based molecules in the discovery of neurological drug development.

CONCLUSION: Due to its broad spectrum of biological activities and favorable pharmacokinetic properties, indole is an impressive scaffold for the treatment of various neurological disorders. Indole demonstrates remarkable therapeutic potential against a range of central nervous system-related conditions, including Alzheimer's disease, epilepsy, migraine, stroke, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and Huntington's disease.},
}

@article {pmid41510572,
year = {2026},
author = {Tang, C and Han, K and Wen, X and Zhang, J and Sun, W and Yue, X and Shi, L and Liu, Z and Zhao, J and Yan, C and Liu, M and Yao, Z and Kong, Z and Liu, Y and Fu, Z and Zhao, X and Yang, Z and Han, M and Chen, C and Xing, Z and Zhou, X and Yang, F and Zhang, Y and Jiang, X},
title = {Synthetic Disaggregators Enhance Central-Peripheral Amyloid-β Clearance in Alzheimer's Disease.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e20002},
doi = {10.1002/adma.202520002},
pmid = {41510572},
issn = {1521-4095},
support = {2024YFA0918400//National Key Research and Development Program of China/ ; 82350125//National Natural Science Foundation of China/ ; 82425056//National Natural Science Foundation of China/ ; 82173763//National Natural Science Foundation of China/ ; 82303810//National Natural Science Foundation of China/ ; ZR2022ZD18//Fundamental Research Funds of Shandong Province/ ; ZR2023QH224//Natural Science Foundation of Shandong Province/ ; 2022M721967//China Postdoctoral Science Foundation/ ; 2024T170524//China Postdoctoral Science Foundation/ ; SYS202202//Shandong Provincial Laboratory Project/ ; NO.tsqnz20221165//Taishan Scholar Foundation of Shandong Province/ ; 2025CXPT177//Key R&D Program of Shandong Province/ ; 2025CXPT177//Key R&D Program of Shandong Province/ ; },
abstract = {Pathogenic amyloid-β (Aβ) accumulation defines Alzheimer's disease (AD), directly inflicting neuronal damage and driving chronic neuroinflammation. While both central microglia and peripheral macrophages are critical for Aβ clearance, their functional impairment in AD inexorably leads to escalating Aβ burden and disease progression. We here report an in situ engineered synthetic Aβ disaggregator (SAD) delivered to macrophages via neuroprotective DHA-based lipid nanoparticles (DLNPs). This platform transcends current therapeutic limitations by not only potently dismantling neurotoxic Aβ aggregates but also by fundamentally reprogramming peripheral macrophages to enhance Aβ clearance. Specifically, our results demonstrate that DLNPs effectively reprogram peripheral macrophages to produce and secrete cerebral-penetrating SAD both in vitro and in vivo. The SAD can promote cerebral Aβ disaggregation, thereby inhibiting neuroinflammatory pathology progression. Moreover, the DLNPs efficiently reprogram the peripheral macrophages to enhance phagocytosis, further facilitating drainage of Aβ and reducing cerebral Aβ accumulation in mouse models. Collectively, these findings uncover a dual-action mechanism of SAD through the synergistic interplay of direct Aβ disaggregation and enhanced macrophage-mediated clearance. In sum, our findings establish that the central-peripheral targeting therapeutic strategy significantly reversed AD pathology, highlighting the therapeutic potential of mRNA-based in situ fusion protein in AD treatment.},
}

@article {pmid41510365,
year = {2026},
author = {Wang, Y and Alexander, GC and Mehta, HB},
title = {Treatment of type 2 diabetes among medicare beneficiaries with and without alzheimer's disease: A retrospective cohort study.},
journal = {Journal of diabetes and metabolic disorders},
volume = {25},
number = {1},
pages = {25},
pmid = {41510365},
issn = {2251-6581},
abstract = {PURPOSE: While Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) commonly co-occur in older adults, little is known regarding whether and how the treatment of T2DM varies by AD status. This study aimed to compare and contrast T2DM treatment among individuals with and without AD.

METHODS: We conducted a retrospective cohort study using 20% Medicare Fee-for-Service claims data from 2016 to 2020. The primary outcome was initiation of any antidiabetic medication within one year of T2DM diagnosis, and we also examined initiation patterns across specific drug classes. We used multivariable logistic regression to estimate adjusted odds ratios for the association between AD and treatment initiation.

RESULTS: Among 388,359 beneficiaries newly diagnosed with T2DM, 9,584 had AD. Within one year, overall treatment initiation was lower for individuals with AD compared to those without. At initiation, individuals with AD were more likely to receive insulin and less likely to receive metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists. In adjusted models, AD was associated with lower odds of antidiabetic treatment initiation, and among those initiating treatment, lower odds of initiating newer agents such as GLP-1 receptor agonists and SGLT2 inhibitors.

CONCLUSION: Beneficiaries with AD were less likely to initiate antidiabetic therapy, particularly newer agents. Future work could explore the basis for these differences.},
}

@article {pmid41510304,
year = {2025},
author = {Wang, Y and Zhou, M and Tang, Z and Xiong, C and Asken, B and Yang, B and Su, J and Zhou, X and Song, Q},
title = {CauReL: Dynamic Counterfactual Learning for Precision Drug Repurposing in Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8206648/v1},
pmid = {41510304},
issn = {2693-5015},
abstract = {Alzheimer's disease has few effective therapies, and decades of amyloid- and tau-focused trials have delivered only modest benefit with substantial toxicity. Drug repurposing using real-world data offers a faster and lower-risk route to new treatments, yet current approaches typically average effects across populations, model disease onset and progression separately, and provide little insight into which patients are most likely to benefit. We present CauReL, a dynamic counterfactual representation learning framework that enables transparent, patient specific estimation of treatment effects from large-scale electronic health records for precision drug repurposing in AD. CauReL first learns balanced latent representations of treated and untreated patients using Integral Probability Metric regularization, then jointly predicts two clinically linked outcomes, incident AD and time from mild cognitive impairment (MCI) to AD, to generate paired counterfactual outcomes for every individual. A counterfactual explanation module quantifies how clinical features shape benefit at the patient level, and uplift trees transform complex heterogeneity into simple, rule-based subgroups suitable for trial enrichment and clinical decision support.Using independent cohorts from OneFlorida + and All of Us, we screened outpatient prescriptions with at least 20 percent exposure among 28,605 individuals with mild cognitive impairment, of whom 4,990 progressed to Alzheimer's disease. CauReL substantially improved covariate balance and distributional overlap across drug cohorts and achieved strong predictive accuracy for both incidence (AUC greater than 0.90) and progression timing (C index 0.81 to 0.84; Spearman 0.80 to 0.86). Twenty drugs showed consistent protective associations, with four emerging as highly reproducible across both networks, the metabolic agents liraglutide and empagliflozin and the neuroactive agents entacapone and amantadine. These drugs were associated with meaningful absolute risk reductions and clinically significant delays in progression from mild cognitive impairment to Alzheimer's disease. Metabolic drugs produced the strongest benefits in individuals with diabetes, obesity, or cardiovascular disease, whereas neuroactive drugs provided broadly consistent protection across most subgroups.CauReL is available as an open source Python package with a companion web server for direct application to new cohorts or disease settings (https://caurel.site/). This work delivers a scalable and interpretable framework for prioritizing repurposable drugs and designing targeted clinical trials for the patients most likely to benefit.},
}

@article {pmid41510223,
year = {2025},
author = {Jiang, L and Tucker, A and Sepehri, C and Patel, D and Wang, Q and Yuan, S and Sherman, E and Chen, Y and Beh, J and Downey, A and Goldberg, D and Gniadzik, W and Ma, X},
title = {Inhibition of N6-Methyladenosine Accumulation by Targeting METTL3 Mitigates Tau Pathology and Cognitive Decline in Alzheimer's Disease.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8379573/v1},
pmid = {41510223},
issn = {2693-5015},
abstract = {Dysregulation of N6-methyladenosine (m6A) modification of RNA has emerged as a novel feature of Alzheimer's disease (AD). Here, we investigate the relationship between m6A modification and AD pathology, and the therapeutic potential of modulating excessive m6A via its "writer" methyltransferase METTL3 in a humanized P301S tau transgenic mouse model of AD (PS19). We observed significantly elevated m6A levels in human post-mortem AD frontal cortex tissue compared to healthy controls, which positively correlated with hyperphosphorylated tau and amyloid-β (Aβ) deposition. These effects were recapitulated in the PS19 tau mice model of AD. Importantly, treatment of PS19 mice with the METTL3 inhibitor STM2457 reduced excessive m6A, alleviated tau pathology, and attenuated neurodegeneration. Behavioral assessments further demonstrated that STM2457-treated PS19 mice exhibited significantly improved learning and memory relative to untreated PS19 mice. Our results identify m6A as a critical contributor to AD pathogenesis and demonstrate that pharmacological inhibition of METTL3 represents a promising therapeutic strategy to improve cognition in AD.},
}

@article {pmid41509358,
year = {2026},
author = {Jati, S and Kal, S and Munoz-Mayorga, D and Tang, K and Sahoo, D and Chen, X and Mahata, SK},
title = {Catestatin ameliorates tauopathy and amyloidogenesis via adrenergic inhibition.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.01.04.697519},
pmid = {41509358},
issn = {2692-8205},
abstract = {Neurodegenerative disorders like Alzheimer's disease (AD), Corticobasal Degeneration (CBD), and Progressive Supranuclear Palsy (PSP) are characterized by Tau aggregation, synaptic dysfunction, neuroinflammation, and progressive cognitive decline. Although metabolic dysregulation and neuropeptide imbalance have been linked to these disorders, the functional consequences of such imbalance and its potential for therapeutic reversal remain poorly understood. Our previous work identified chromogranin A (CgA), which encodes a pro-hormone for several metabolic peptides, as a key regulator of Tau pathology. Here, we investigate Catestatin (CST), a CgA-derived peptide that is a potent inhibitor of catecholamine release and has been shown to increase insulin sensitivity and lower peripheral blood pressure. We report significant reductions in CST levels in the hippocampus and cortex of AD brains, as well as in the frontal cortex of CBD and the basal ganglia of PSP. Supplementing CST in cortical neuronal cultures and organotypic slice cultures (OTSC) decreased Tau phosphorylation and aggregation. In vivo , CST administration in PS19 Tauopathy mice reduced pathological Tau species, attenuated gliosis, and improved cognitive function. CST treatment also lowered amyloid plaque burden and neuroinflammation in 5xFAD mice. Mechanistically, CST decreased epinephrine (EPI) levels in both PS19 and 5xFAD mice and suppressed downstream protein kinase A (PKA) hyperactivation in PS19 and OTSC. These findings reveal a previously unrecognized neuropeptidergic mechanism linking CST deficiency to elevated adrenergic receptor (ADR)-EPI-PKA stress signaling and Tauopathy-driven neurodegeneration, suggesting CST replacement as a promising therapeutic approach.},
}

@article {pmid41509252,
year = {2026},
author = {Jesudason, CD and Rangel-Barajas, C and Beach, CJ and Beck, DE and Caballero-Floran, IH and Clayton, WB and Da Silva, L and David, JC and Doolen, S and Faulkner, AN and Hamdani, AK and Huhe, H and Huynh, K and Imhoff, RD and Javens-Wolfe, J and Mason, ER and Moussaif, M and Singhal, K and Soni, DM and van Buuren-Milne, M and Williams, SP and Angus, SP and Chu, S and Dage, JL and Hipskind, PA and Johnson, TS and Kaddurah-Daouk, R and Lamb, BT and Meikle, PJ and Mesecar, AD and Palkowitz, AD and Quinney, SK and Sukoff Rizzo, SJ and Oblak, AL and Richardson, TI},
title = {Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer's Disease Models.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.31.697127},
pmid = {41509252},
issn = {2692-8205},
abstract = {Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1), encoded by the gene INPP5D, is a lipid phosphatase that negatively regulates immune receptor signaling in hematopoietic cells and microglia. Here, we describe a pyridyl-pyrazole-piperidine scaffold and the lead compound 3-((2-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine (32), which demonstrates SHIP1 target engagement, brain exposure, and evidence of a central pharmacodynamic response in vivo . Structure-activity relationship studies, guided by biochemical and cellular assays using multiple human and murine protein constructs and cells, identified SHIP1-active ligands. A thermal shift assay using full-length SHIP1 was used to assess compounds for cellular target engagement, while studies in IL-4 conditioned THP-1 cells was used to demonstrate changes in downstream AKT signaling. Targeted lipidomics revealed changes in the overall phosphoinositide pool consistent with SHIP1 target engagement and reduction of phospho-AKT levels. In a protein-lipid overlay assay, compound 32 induced changes in the relative association of SHIP1 with multiple phosphatidylinositols on a membrane surface. In high-content cellular imaging assays, compound 32 enhanced the uptake of myelin/membrane debris and fibrillar amyloid by primary murine microglia, phenocopying a genetic model with reduced SHIP1 expression. Finally, oral administration of compound 32 resulted in brain exposure sufficient to alter gene expression and reduce IL-1β levels as pharmacodynamic markers of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimer's disease. Collectively, these results define a scaffold with SHIP1 target engagement, CNS exposure, and in vivo activity, providing a foundation for the optimization of brain-penetrant SHIP1 ligands suitable for further mechanistic studies and therapeutic development for the treatment of Alzheimer's disease.},
}

@article {pmid41509242,
year = {2025},
author = {Kumari, R and Bowen, C and Srivastava, U and Brandelli, AD and Kumar, P and Kour, D and Malepati, S and Jang, WE and Bromwich, M and Zeng, H and Sing, A and Sloan, SA and Wulff, H and Rangaraju, S},
title = {Kv1.3 inhibition alleviates neuropathology via neuroinflammatory and resilience pathways in a mouse model of Aβ pathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.25.696456},
pmid = {41509242},
issn = {2692-8205},
abstract = {Inhibition of voltage-gated potassium channel Kv1.3 is a therapeutic strategy to curb microglia-mediated neuroinflammation in neurodegeneration, although the cellular and signaling mechanisms of disease-modification by Kv1.3 blockers are unclear. In this study, we delineate protective mechanisms of Kv1.3 blockade in a mouse model of Alzheimer's disease (AD) pathology using comprehensive transcriptomics and proteomics profiling of brain, corresponding with neuropathological effects of two translationally relevant Kv1.3 blockers, namely small molecule PAP-1 and peptide ShK-223. Following 3 months of treatment, both molecules reduced Ab plaque burden. Single nuclear RNA seq (snRNA seq) of brain nuclei showed that PAP-1 disproportionately impacted oligodendrocytes and microglia and increased crosstalk between neurons and astrocytes with endothelial cells. In contrast, ShK-223 had pronounced effects on glutamatergic neurons and astrocytes. Both blockers increased expression of myelination genes in oligodendrocytes and synaptic genes in neurons. Neuroprotective effects of PAP-1 were further confirmed by bulk brain transcriptomics and proteomics whereby PAP-1 increased levels of synaptic, cognitive resilience and mitochondrial proteins, while decreasing glial and immune pathways including STAT1/3 phosphorylation. Using proximity labeling and co-immunoprecipitation, we found that Kv1.3 interacts with STAT1/3 in microglia. Using microglial cell lines and primary microglia, we discovered a preferential functional coupling between Kv1.3 and type 2 but not type 1 IFN signaling. Brain-level disease modification by Kv1.3 blockade was reflected in the cerebrospinal fluid (CSF) via reduced levels of neurofilament-light (NEFL) and resilience protein RPH3A, both of which are increased in human AD CSF. Together, this study demonstrates functional links between Kv1.3 channels and type 2 IFN signaling and reveals distinct cellular effects of Kv1.3 blockers in AD pathology that correspond with reduced neuropathology and neuroinflammation, augmentation of resilience and neuro-vascular pathways, along with biomarkers of therapeutic effect.},
}

@article {pmid41508224,
year = {2025},
author = {Ma, YJ and Deng, SX and Liao, ZH and Gao, MH and Ding, HX and Xu, ZQ and Lu, YT and Yang, C and Wang, Q},
title = {[Treatment of Alzheimer's disease from gut-brain interactions based on theory of "spleen deficiency leading to obstruction of nine orifices"].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {19},
pages = {5330-5339},
doi = {10.19540/j.cnki.cjcmm.20250618.501},
pmid = {41508224},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy/physiopathology/metabolism ; Humans ; *Brain/physiopathology/drug effects/metabolism ; *Spleen/physiopathology/drug effects ; Animals ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use ; Gastrointestinal Microbiome ; },
abstract = {Alzheimer's disease(AD) is the most common form of dementia. The decline in sensory function is associated with pathological damage in specific brain regions during the early stages of AD. Such decline often precedes cognitive impairment, worsens as the pathology progresses, and constitutes a high-risk factor for the onset of AD. According to traditional Chinese medicine(TCM), all orifices are connected to the brain, and the brain governs all orifices. The mind originates from and depends on both the brain and orifices, with their physiological and pathological states being closely interconnected. In AD, dysfunction of the sensory orifices is closely linked to the later-stage manifestations of impaired mental clarity and consciousness. The theory that "spleen deficiency leading to obstruction of nine orifices" emphasizes that insufficiency of the spleen and stomach is the root cause of orifice dysfunction. Both internal and external pathogenic factors in AD can damage the spleen and stomach, leading to the abnormal movement of turbid substances generated by these organs, which may transform into turbid toxins. This, in turn, gradually impairs the orifices, brain, and mind, thereby exacerbating the progression of AD. The digestive, absorptive, and transport functions of the spleen and stomach are similar to those of the gut microbiota. Spleen deficiency is a core pathological factor in diseases associated with gut microbiota dysbiosis. Such dysbiosis can lead to dysfunction in the neural, metabolic, and immune pathways involved in gut-brain interactions, constituting the biological basis for the TCM concept that "spleen deficiency leading to obstruction of nine orifices". Under the guidance of this theory, employing spleen-strengthening and cognition-enhancing drugs alongside aromatic orifice-opening drugs to support spleen function, and using ingredients that promote dampness elimination, lubrication, and blood stasis resolution to dispel pathogenic factors from the orifices, can help restore the structural balance of the gut microbiota, regulate related metabolic and immune dysfunctions, and ultimately delay the progression of AD. This article explores the etiology, pathogenesis, and therapeutic strategies of AD based on the theory of "spleen deficiency leading to obstruction of nine orifices", and interprets its biological significance from the perspective of gut-brain interactions, aiming to provide new insights for the prevention and treatment of AD.},
}

*Alzheimer Disease/drug therapy/physiopathology/metabolism
Humans
*Brain/physiopathology/drug effects/metabolism
*Spleen/physiopathology/drug effects
Animals
Medicine, Chinese Traditional
Drugs, Chinese Herbal/therapeutic use
Gastrointestinal Microbiome

@article {pmid41508200,
year = {2025},
author = {Zhang, YX and Wang, J and Chen, QQ and Zhang, JL and Wang, Q and Long, YL and Zhou, SJ and Gong, ZP and Zheng, L and Huang, Y and Li, YT},
title = {[Study on quality markers of Pleione yunnanensis for "same treatment for different diseases" in liver inflammation and Alzheimer's disease based on UHPLC fingerprint and network pharmacology].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {20},
pages = {5684-5696},
doi = {10.19540/j.cnki.cjcmm.20250710.202},
pmid = {41508200},
issn = {1001-5302},
mesh = {Network Pharmacology ; *Drugs, Chinese Herbal/chemistry/therapeutic use ; *Alzheimer Disease/drug therapy/genetics/metabolism ; Chromatography, High Pressure Liquid/methods ; Humans ; Molecular Docking Simulation ; Biomarkers/analysis ; Quality Control ; },
abstract = {This study aims to screen quality markers(Q-markers) of Pleione yunnanensis for the treatment of liver inflammation and Alzheimer's disease(AD) based on the concept of "same treatment for different diseases" using ultra-high-performance liquid chromatography(UHPLC) fingerprinting combined with network pharmacology and molecular docking, and to perform quantitative analysis of the identified Q-markers. The UHPLC fingerprints of 15 batches of P. yunnanensis were established and subjected to similarity evaluation, cluster analysis(CA), principal component analysis(PCA), and orthogonal partial least squares discriminant analysis(OPLS-DA) to identify characteristic components responsible for quality variations. Network pharmacology and molecular docking were employed to explore the potential active components, related targets, and signaling pathways underlying the "same treatment for different diseases" mechanism for liver inflammation and AD. Based on the criteria of effectiveness, specificity, and measurability, Q-markers of P. yunnanensis were identified and quantified. Ten common peaks were identified in the UHPLC fingerprints of 15 batches, with eight components identified. Similarity scores ranged from 0.774 to 0.987. Chemical pattern recognition analysis identified that shancigusin H, militarine, and gymnoside Ⅴ were the major characteristic components contributing to quality differences among batches. RESULTS:: of network pharmacology and molecular docking revealed that dactylorhin A and militarine were the key active components exerting anti-inflammatory and neuroprotective effects. These components acted on 13 core targets, including SRC, CASP3, and CTNNB1, and regulated signaling pathways such as the PI3K-Akt signaling pathway and arachidonic acid metabolism. Based on the effectiveness, specificity, and measurability of Q-marker, dactylorhin A and militarine were selected as the Q-markers of P. yunnanensis. Quantitative analysis demonstrated that the content of dactylorhin A ranged from 0.527% to 2.21%, and militarine ranged from 0.731% to 2.58% across the 15 batches. The UHPLC fingerprint method and Q-marker-based quantification approach are robust and reliable, providing experimental evidence for quality control and standardization of P. yunnanensis.},
}

Network Pharmacology
*Drugs, Chinese Herbal/chemistry/therapeutic use
*Alzheimer Disease/drug therapy/genetics/metabolism
Chromatography, High Pressure Liquid/methods
Humans
Molecular Docking Simulation
Biomarkers/analysis
Quality Control

@article {pmid41508178,
year = {2025},
author = {Hou, WX and Liu, YX and Miao, JR and Zhu, ZK and Yin, Y and Liu, JL and Zhao, DY},
title = {[Mechanism of Liuwei Dihuang Pills in enhancing GPNMB expression to regulate FcγRⅡB/c-Src pathway for prevention and treatment of Alzheimer's disease].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {21},
pages = {6062-6071},
doi = {10.19540/j.cnki.cjcmm.20250805.401},
pmid = {41508178},
issn = {1001-5302},
mesh = {Animals ; *Drugs, Chinese Herbal/administration & dosage ; *Alzheimer Disease/drug therapy/genetics/metabolism/prevention & control ; Male ; Mice ; *Membrane Glycoproteins/genetics/metabolism ; Humans ; Signal Transduction/drug effects ; *src-Family Kinases/metabolism/genetics ; Hippocampus/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Memory/drug effects ; Eye Proteins ; },
abstract = {This study investigated the effect of Liuwei Dihuang Pills on the Fcγ receptor Ⅱ-b(FcγRⅡB)/c-Src tyrosine kinase(c-Src) pathway in senescence-accelerated mouse prone 8(SAMP8) by regulating the expression of the glycoprotein non-metastatic melanoma protein B(GPNMB) and explored the mechanism of the kidney-tonifying and essence-strengthening therapy in the treatment of Alzheimer's disease.(1) For the effects of Liuwei Dihuang Pills on the learning and memory ability, hippocampal β-amyloid protein(Aβ), GPNMB, and autophagy function in SAMP8 mice, eight seven-month-old male senescence-accelerated mouse resistant 1(SAMR1) mice were used as a control group, and 16 male SAMP8 mice of the same age were randomly divided into a model group and a Liuwei Dihuang Pills group. The Liuwei Dihuang Pills group was given 2.36 g·kg~(-1) concentrated Liuwei Dihuang Pills solution by gavage, while the control group and the model group were given the same volume of normal saline twice a day for four consecutive weeks. The learning and memory ability of mice in each group was detected by the Morris water maze experiment; the expression level of Aβ in the hippocampus of mice were detected by enzyme-linked immunosorbent assay(ELISA) and immunohistochemistry; the expression of GPNMB in the hippocampus of mice was detected by immunofluorescence and Western blot; the expression level of ubiquitin-binding protein p62 and microtubule-associated protein light chain 3(LC3) Ⅱ/LC3Ⅰ in the hippocampus of mice was measured by Western blot.(2) For the regulatory effect of GPNMB on the FcγRⅡB/c-Src pathway, eight seven-month-old male SAMR1 mice were used as a control group, and 24 male SAMP8 mice of the same age were randomly divided into a model group, an LV-Vector group, and an LV-GPNMB~(OE) group. The bilateral hippocampus of the LV-Vector group and LV-GPNMB~(OE) group was injected with LV-Vector and LV-GPNMB~(OE) of 2 μL/each side, respectively. Western blot was used to detect the expression level of p62, LC3Ⅱ/LC3Ⅰ, FcγRⅡB, Src homology 2 protein tyrosine phosphatase 1(SHP-1), and c-Src proteins in the hippocampus of mice.(3) For the effect of Liuwei Dihuang Pills in regulating the FcγRⅡB/c-Src pathway by increasing the GPNMB expression, 32 seven-month-old male SAMP8 mice were randomly divided into a model group, a Liuwei Dihuang Pills group, a Liuwei Dihuang Pills + LV-NC group, and a Liuwei Dihuang Pills + LV-shGPNMB group. The bilateral hippocampus of the Liuwei Dihuang Pills + LV-NC group and Liuwei Dihuang Pills + LV-shGPNMB group was injected with LV-NC and LV-shGPNMB, respectively, before the drug treatment. Western blot was used to detect the expression level of p62, LC3Ⅱ/LC3Ⅰ, FcγRⅡB, SHP-1, and c-Src proteins in the hippocampus of mice. The results showed that(1) compared with those of the control group, the escape latency of the model group was significantly increased, and the time spent in the target quadrant and the effective area was significantly decreased. The expression level of Aβ, GPNMB, and p62 in the hippocampus was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. Compared with those of the model group, the escape latency of the Liuwei Dihuang Pills group was significantly shortened, and the time spent in the target quadrant and the effective area was significantly increased. The level of Aβ was significantly decreased, and the expression level of GPNMB was significantly increased. The expression level of p62 was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased.(2) Compared with those of the control group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src proteins in the hippocampus of the model group was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. Compared with those of the model group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the LV-GPNMB~(OE) group was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased.(3) Compared with those of the model group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the Liuwei Dihuang Pills group was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased. Compared with those of the Liuwei Dihuang Pills group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the Liuwei Dihuang Pills + LV-shGPNMB group was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. These results indicate that Liuwei Dihuang Pills can inhibit the FcγRⅡB/c-Src pathway by up-regulating the GPNMB expression, thereby increasing autophagy levels, enhancing neuroprotective ability, and alleviating Alzheimer's disease.},
}

Animals
*Drugs, Chinese Herbal/administration & dosage
*Alzheimer Disease/drug therapy/genetics/metabolism/prevention & control
Male
Mice
*Membrane Glycoproteins/genetics/metabolism
Humans
Signal Transduction/drug effects
*src-Family Kinases/metabolism/genetics
Hippocampus/drug effects/metabolism
Amyloid beta-Peptides/metabolism
Memory/drug effects
Eye Proteins

@article {pmid41508060,
year = {2025},
author = {Sun, CX and Han, XY and Xiao, YT and Liu, YX and Ye, TY},
title = {[Research progress on prevention and treatment of Alzheimer's disease with Danggui Shaoyao San].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {22},
pages = {6215-6226},
doi = {10.19540/j.cnki.cjcmm.20250626.601},
pmid = {41508060},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy/prevention & control/metabolism ; *Drugs, Chinese Herbal/therapeutic use/administration & dosage ; Humans ; Animals ; },
abstract = {Alzheimer's disease is a neurodegenerative disorder associated with aging. In traditional Chinese medicine(TCM), it is classified as a syndrome of root deficiency and branch excess. Danggui Shaoyao San, a classic formula traditionally used to treat gynecological disorders, has the effects of promoting blood circulation, removing blood stasis, opening orifices, awakening the mind, strengthening the spleen, resolving phlegm, and tonifying Qi to nourish the spirit. Modern clinical studies have found that Danggui Shaoyao San can slow the progression of Alzheimer's disease and has great potential for clinical application. Recent studies indicate that Danggui Shaoyao San treats Alzheimer's disease through multi-target and multi-level mechanisms. These include clearing amyloid β(Aβ) plaques and abnormally phosphorylated tau protein, maintaining brain-gut homeostasis, reducing oxidative stress, and regulating autophagy. Its key components, paeoniflorin and ferulic acid, have also been reported to exert antioxidant, anti-inflammatory, and anti-apoptotic effects, eliminate pathological products, and regulate the cholinergic system in the brain. This paper traces the classic formula of Danggui Shaoyao San, conducts a theoretical integration of ancient and modern medical systems, and systematically summarizes and analyzes the research related to the treatment of Alzheimer's disease using Danggui Shaoyao San and its key components. It aims to provide a valuable reference for further research and modern application of Danggui Shaoyao San in the treatment of Alzheimer's disease.},
}

*Alzheimer Disease/drug therapy/prevention & control/metabolism
*Drugs, Chinese Herbal/therapeutic use/administration & dosage
Humans
Animals

@article {pmid41507065,
year = {2026},
author = {De Rui, M and Salerno Trapella, G and Ceolin, C and Ceccato, F and Antonelli, G and Ravelli, A and Andreuzza, R and Conti, E and Sarlo, M and Coin, A and Zanforlini, BM and Bertocco, A and Curreri, C and Tizianel, I and Mapelli, D and Sergi, G and Devita, M},
title = {Effect of cognitive training on cortisol levels in patients with neurocognitive disorders.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbaf243},
pmid = {41507065},
issn = {1758-5368},
abstract = {OBJECTIVES: Elevated cortisol levels are linked to a greater risk and faster progression of neurocognitive disorders (NCDs). While interventions such as exercise and mindfulness have shown benefits in reducing cortisol, the impact of cognitive training (CT) on cortisol regulation remains unexplored. This study investigated whether CT affects cortisol levels and secretion patterns in individuals with minor or major NCD and compared its effects with those of pharmacological treatment.

METHODS: Sixty-two older adults with NCD and 43 healthy controls were recruited from the University Hospital of Padua in Italy. Among patients with NCD, 34 underwent CT (CT-NCD group), and 28 received pharmacological treatment (PH-NCD group). Salivary cortisol was measured at six points during the day, at baseline, and at 3 months (T1) and 6 months (T2) post-intervention.

RESULTS: Compared with pharmacological treatment (PH), CT showed a larger percentage decrease of daily cortisol exposure (AUC) from baseline; however, the between-group difference did not remain statistically significant after covariate adjustment, and the only robust time-point effect was in the afternoon (F(1,47)=5.13; p = 0.028). Morning values decreased within groups, but between-group differences in the CAR were not significant; at bedtime, CT showed only a trend towards lower cortisol than PH (p = 0.071). Median morning values changed from 7.75 to 6.20 in CT and from 5.80 to 5.15 in PH.

DISCUSSION: CT may help lower cortisol levels and enhance cognitive function in NCD patients, suggesting its potential as a nonpharmacological tool to modulate hypothalamic-pituitary-adrenal axis activity. Larger randomized studies are needed to confirm and extend these findings.},
}

@article {pmid41506855,
year = {2025},
author = {Lizama, BN and Caro, VD and Cho, E and Caldwell, J and Pandey, K and Duong, DM and Seyfried, NT and Grundman, M and Caggiano, AO and Teunissen, CE and Hamby, ME},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107075},
doi = {10.1002/alz70856_107075},
pmid = {41506855},
issn = {1552-5279},
mesh = {Humans ; Biomarkers/blood ; Double-Blind Method ; Male ; *Alzheimer Disease/drug therapy/blood ; Female ; Aged ; Proteomics ; Cognitive Dysfunction/drug therapy/blood ; Receptors, sigma ; },
abstract = {BACKGROUND: Participants with Alzheimer's disease (AD) treated with sigma-2 receptor (S2R) modulator zervimesine (CT1812) exhibited 39% slowing of cognitive decline (ADAS-Cog11) compared to placebo in the mITT cohort of the SHINE trial (NCT03507790, COG0201). The pre-specified below-median pTau217 subgroup showed 95% slowing with zervimesine, and significant decrease in plasma-GFAP, a neuroinflammation biomarker, compared to placebo (-28.35 ± 11.687 SEM, p = 0.0186). Given favorable outcomes with zervimesine treatment in the below-median pTau217 subgroup, a plasma proteomic biomarker sub-study assessing correlation of plasma proteins with plasma-GFAP was performed to elucidate protective mechanisms of zervimesine.

METHOD: SHINE was a Phase 2 randomized, double-blind, placebo-controlled study. Participants (N = 152) received a daily oral dose of zervimesine (100 or 300 mg) or placebo for 6-months (end-of-study, EOS). A proteomics sub-study of 60 participants was performed using tandem-mass tag mass spectrometry (TMT-MS) of plasma collected at baseline and EOS, with downstream analyses from treatment-compliant participants (mITT N = 57). For subgroup analysis, plasma from participants with median baseline plasma p-Tau217 concentration (ALZpath, SIMOA) <1pg/mL was analyzed (N = 24). Change from baseline (CFB) was calculated, and Pearson correlation analysis was performed with plasma-GFAP (assessed via SIMOA) and protein levels, assessed via proteomics, from either 1) placebo and drug-treated (all-participants analysis) or 2) drug-only treated participants (drug-only analysis). Pathway analysis was performed on correlated proteins (p≤0.05).

RESULT: TMT-MS of plasma detected 1674 proteins, from which 45 were correlated to GFAP in the all-participants analysis and 284 in drug-only analysis (p≤0.05). Thirteen proteins were overlapping between the all-participants and drug-only analyses, including inflammation-related proteins ALOX12 and CTSG, and lysosomal protein LAMP1. To further home in on pharmacodynamic biomarkers of zervimesine, the 13 overlapping correlates were excluded, allowing for 271 proteins specifically correlated with drug treatment to be identified (p≤0.05). These proteins were enriched in vesicle-mediated transport and inflammation-related pathways (FDR≤0.05).

CONCLUSION: The correlates identified may represent an inflammatory signature tied to the decreased neuroinflammation (plasma-GFAP) with zervimesine in AD patients observed in the pTau217 biomarker-defined subgroup (below the median). Results support a role for zervimesine in decreasing neuroinflammation and the continued clinical development of zervimesine for AD.},
}

Humans
Biomarkers/blood
Double-Blind Method
Male
*Alzheimer Disease/drug therapy/blood
Female
Aged
Proteomics
Cognitive Dysfunction/drug therapy/blood
Receptors, sigma

@article {pmid41506734,
year = {2026},
author = {, and , },
title = {[Guidelines for the management of chronic insomnia comorbid with common neuropsychiatric disorders in adults (2025 edition)].},
journal = {Zhonghua nei ke za zhi},
volume = {65},
number = {1},
pages = {18-44},
doi = {10.3760/cma.j.cn112138-20250911-00539},
pmid = {41506734},
issn = {0578-1426},
support = {2021YFC2501400//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Sleep Initiation and Maintenance Disorders/therapy/epidemiology/complications ; *Mental Disorders/therapy/complications/epidemiology ; Comorbidity ; Adult ; Parkinson Disease ; },
abstract = {Chronic insomnia frequently co-occurs with common neuropsychiatric disorders, including migraine, stroke, Alzheimer's disease, Parkinson's disease, epilepsy, generalized anxiety disorder, depressive disorder, body distress disorder, post-traumatic stress disorder, and disorders due to use of alcohol. The prevalence of these neuropsychiatric disorders is hiher among patients with chronic insomnia than in the general population, and the conditions mutually exacerbate each other. Comorbidities not only exacerbate the severity and increases the relapse risk of each condition but also lead to a poorer prognosis, more severe impairment of social functioning, a higher all-cause mortality risk, and greater treatment challenges. Therefore, the Sleep Disorders Group, Chinese Society of Neurology and Sleep Medicine Group,China Neurologist Association have convened experts in relevant fields, based on current medical evidence, to establish guideline for the management of Chinese adults with chronic insomnia comorbid with the aforementioned 10 categories of common neuropsychiatric disorders. The aim is to standardize clinical practice and improve treatment effectiveness and cure rates.},
}

Humans
*Sleep Initiation and Maintenance Disorders/therapy/epidemiology/complications
*Mental Disorders/therapy/complications/epidemiology
Comorbidity
Adult
Parkinson Disease

@article {pmid41506719,
year = {2025},
author = {Song, Z and Huang, X and Liu, J and Chen, J and Johnson, TS and Zhang, J and Huang, K},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107088},
doi = {10.1002/alz70856_107088},
pmid = {41506719},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnosis/classification/metabolism ; *Biomarkers ; Male ; Female ; Aged ; Proteomics ; Algorithms ; Disease Progression ; DNA Methylation ; },
abstract = {BACKGROUND: Distinguishing Alzheimer's Disease (AD) subtypes can improve disease diagnosis, treatment, and management. This study uses Graph Attention Networks (GAT) and a cross-attention algorithm to integrate multi-omics data and characterize distinct AD subtypes.

METHOD: Three omics datasets, including transcriptomics, proteomics, DNA methylation, and clinical information from 156 Religious Orders Study and Rush Memory and Aging Project (ROSMAP) patients and controls, were integrated using a Graph Attention Network (GAT) and a cross-attention mechanism. GAT encoders generated embeddings for each omics graph, which were integrated via pairwise cross-attention and combined with clinical data through projection layers. A multi-task loss combining cross-entropy and reconstruction losses was used for training, yielding integrated embeddings representing the molecular complexity of AD (Figure 1). Pseudotime for all patients was calculated using the Partition-based Graph Abstraction (PAGA) method to compare disease progression trajectories across subtypes identified by KMeans. Differentially expressed genes (DEGs) and clinical differences between AD-enriched clusters were evaluated to characterize AD subtypes, and gene set enrichment analysis identified molecular functions, biological processes, and cellular components enriched among DEGs.

RESULT: Four clusters were identified: two enriched in controls and two in AD (Figure 2). This study focuses on comparing the two AD subtypes. Pseudotime analysis showed significant trajectory differences among all clusters, particularly between the AD subtypes (adjusted p < 0.01), indicating distinct disease trajectories. Demographic factors age, sex, and APOE status, showed no significant differences between the two subtypes. Cognitive status differed significantly, with one AD subtype including more patients with mild cognitive impairment (MCI). Additionally, 75 DEGs between the two subtypes were identified (FDR < 0.05 and logFC > 0.7), along with 126 significant molecular processes, 3 biological functions, and 38 cell components were identified, with adjusted p-values < 0.1 (Figure 3).

CONCLUSION: The pipeline integrated multimodal omics data and successfully identified two AD subtypes with distinct disease progression. The 75 DEGs are enriched cellular response to copper ions, hormone activity, and mitochondrial respiratory chain complex I and clathrin-sculpted vesicles, which we believe play important roles in AD pathogenesis and differentiate the two subtypes.},
}

Humans
*Alzheimer Disease/genetics/diagnosis/classification/metabolism
*Biomarkers
Male
Female
Aged
Proteomics
Algorithms
Disease Progression
DNA Methylation

@article {pmid41506617,
year = {2025},
author = {Verbel, D and Niu, H and Reyderman, L and Irizarry, MC and Sachdev, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e107102},
doi = {10.1002/alz70856_107102},
pmid = {41506617},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *alpha-Synuclein/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; Male ; Female ; Aged ; Disease Progression ; *Cognitive Dysfunction/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Lewy Body Disease/cerebrospinal fluid ; Positron-Emission Tomography ; },
abstract = {BACKGROUND: Existing copathologies, such as Lewy body (LB) disease, can introduce heterogeneity to AD pathogenesis and presentation of symptoms and likely influence disease progression. A seed amplification assay (SAA) that detects aggregated, misfolded α-synuclein (α-syn) can detect LB. Incorporation of SAA can characterize disease heterogeneity in AD and potentially predict disease progression.

METHODS: A validated SAA was used to characterize α-syn SAA status (Amprion Clinical Laboratory) in baseline CSF samples collected from a Phase 3 program for elenbecestat in subjects with MCI or mild dementia due to AD (NCT02956486). Samples were selected by PET visual read status. The sample set was enriched using subjects considered to be progressors or non-progressors based on change in cognition (CDR-SB) at 18 months, before assessment of SAA status. Results of α-syn status were reported as Detected, Not Detected, or Indeterminate. The proportion of samples defined as Detected and Not Detected were summarized by amyloid status. Cognition, at baseline and longitudinally, was summarized by amyloid and α-syn status. Available baseline A/T/N biomarkers were also summarized and compared.

RESULTS: Among the 201 samples that were included in the analyses, 15% of amyloid+ and 8% of amyloid- MCI/early AD subjects were determined to be SAA+ and hence determined to have LB copathology. In comparison, in ADNI, 17% of cognitively unimpaired (CU) subjects; 20% of MCI subjects and 39% of AD subjects had synuclein copathology (Tosun et al Alzheimer's Dement. 2024). In BioFinder2, synuclein copathology was detected in 8%, 17% and 23% of CU, MCI, and AD subjects, respectively (Palmqvist et al and Quadalti et al Nature Medicine 2023). The longitudinal trajectory of amyloid positive subjects with α-syn copathology seemed to have faster cognitive decline in natural history studies. In the Phase 3 samples, the longitudinal cognitive trajectory showed trend towards faster decline over 18 months in the amyloid+ subjects with α-syn copathology; however, this did not appear significant.

CONCLUSION: LB, a common copathology of AD, may be a source of heterogeneity. Incorporation of SAA, a specific biomarker of LB-pathology, can help account for disease heterogeneity and potentially improve assessment of treatment response in amyloid and synuclein status confirmed AD target population.},
}

Humans
*Biomarkers/cerebrospinal fluid
*alpha-Synuclein/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnosis
Male
Female
Aged
Disease Progression
*Cognitive Dysfunction/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Lewy Body Disease/cerebrospinal fluid
Positron-Emission Tomography

@article {pmid41506537,
year = {2026},
author = {Liang, YZ and Jiang, MZ and Xu, XT and Zhu, T and Guo, H and Ding, L and Zhong, H and Bao, J and Qin, LQ and Li, YH},
title = {Ameliorating effect and mechanism of p-coumaric acid liposome on cognitive dysfunction and mitochondrial damage under intermittent hypoxia.},
journal = {Life sciences},
volume = {},
number = {},
pages = {124197},
doi = {10.1016/j.lfs.2026.124197},
pmid = {41506537},
issn = {1879-0631},
abstract = {AIMS: Alzheimer's disease (AD) has become a global public health problem. Mitochondrial dysfunction contributes to AD pathogenesis, and adequate oxygen supply is essential to maintain mitochondrial homeostasis. P-coumaric Acid (CA) is a polyphenol with anti-hypoxia and anti-AD properties. In this study, CA was formulated into a biomimetic liposome (CA-Lip) to enhance its therapeutic efficacy, and the underlying mechanisms were studied.

MATERIALS AND METHODS: APP/PS1 mice were divided into four groups: AD group, hypoxia treatment group (AD-HY group), hypoxia + CA treatment group (CA group), hypoxia + CA-Lip treatment group (CA-Lip group). Age-matched wild-type littermates were used as controls. Mice in the hypoxia treatment groups were exposed to a hypoxia chamber for 6 h daily for 8 weeks. Cognitive performance and mitochondrial function were subsequently evaluated to determine the ameliorating effects and mechanisms of CA-Lip.

RESULTS: Cognitive impairment and mitochondrial dysfunction were more pronounced in the AD-HY group than in the AD group. CA-Lip produced greater neuroprotective effects than CA. Mechanistic analyses showed that CA-Lip reduced amyloid-β (Aβ) accumulation, enhanced mitochondrial biogenesis (upregulation of PGC-1α expression), maintained mitochondrial dynamics (upregulation of MFN2 expression, and downregulation of Drp1 expression), inhibited excessive mitophagy (downregulation of PINK1 and Parkin expression), enhanced cell autophagy (upregulation of ATG7 and LC3B expression and downregulation of mTOR and P62 expression), and reduced neuronal apoptosis.

CONCLUSIONS: CA-Lip effectively ameliorates hypoxia-induced cognitive impairment by reducing Aβ generation and improving mitochondrial function.},
}

@article {pmid41506530,
year = {2025},
author = {Bali, D and Janelidze, S and Salvadó, G and Ashton, NJ and Palmqvist, S and Rodriguez, JL and Stomrud, E and Mattsson-Carlgren, N and Hansson, O},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105473},
doi = {10.1002/alz70856_105473},
pmid = {41506530},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Amyloid beta-Peptides/blood ; *tau Proteins/blood ; Aged ; Neurofilament Proteins/blood ; *Cognitive Dysfunction/blood ; Glial Fibrillary Acidic Protein/blood ; *Alzheimer Disease/blood ; Sweden ; Peptide Fragments/blood ; Longitudinal Studies ; Aged, 80 and over ; Middle Aged ; Cohort Studies ; },
abstract = {BACKGROUND: Blood based biomarkers of Alzheimer´s disease (AD) that exhibit a high degree of change over time and are associated with deterioration in cognitive performance and atrophy could be useful in clinical trials to monitor treatment responses. In this study we investigated the longitudinal changes in plasma p-tau biomarkers, amyloid-beta(Aβ)42/Aβ40, Glial fibrillary acidic protein (GFAP) and Neurofilament light (NfL) and assessed associations between changes in these biomarkers and cognitive decline.

METHOD: We included 718 participants (cognitively unimpaired (CU) or Mild Cognitive Impairment (MCI)) from the Swedish BioFINDER-1 cohort who were followed upto 8 years. Plasma samples were analyzed for p-tau217 (Lilly immunoassay), NfL, GFAP, p-tau181 (Roche Prototype immunoassay), N-terminal tau (NTA-tau;Simoa immunoassay) and Aβ42/Aβ40 (mass spectrometry). We analyzed changes in individual plasma biomarker levels using linear mixed-effects models, incorporating Aβ status*time interaction. Associations between biomarker slopes and cognitive decline (assessed with mini-mental state examination [MMSE] and modified Preclinical Alzheimer´s Cognitive Composite[mPACC]) were assessed. An optimal model combining several biomarker slopes was also evaluated.

RESULT: In the whole cohort, p-tau217, NfL, GFAP and p-tau181 were significantly increased over time showing more accelerated increase in Aβ+ than Aβ- participants. The strongest effect was seen for p-tau217 (β=0.200, 95%CI0.17-0.23;p<0.001) followed by NfL(β=0.047, 95%CI0.015-0.08;p=0.005), GFAP(β=0.068, 95%CI0.046-0.09; p = <0.001) and p-tau181(β=0.089, 95%CI0.051,0.13;p<0.001)(Table 1, Figure 1). In individual models, slopes of all biomarkers were associated with change in MMSE and mPACC in the whole cohort. In the Aβ+ group, all biomarkers except NTA-tau demonstrated significant associations with longitudinal MMSE and mPACC. The strongest associations were seen for p-tau217 in both the whole cohort [MMSE (β=-0.353, 95%CI -0.40-(-0.31)]; for interaction between p-tau217 slope and time to predict cognitive scores; mPACC(β=-0.226 95%CI-0.26-(-0.19);p<0.001) and in the Aβ+ group [MMSE(β=-0.336, 95%CI-0.40-(-0.27); mPACC(β=-0.245, 95%CI-0.31-(-0.18);p<0.001)] (Tables 2-5). The best performing model for predicting longitudinal MMSE and mPACC included the interaction between p-tau217 slope (but not other biomarker slopes) and time, both in the whole cohort [MMSE(β=-0.340,95%CI -0.39-(-0.30)); mPACC(β=-0.238, 95%CI-0.27-(-0.20);p<0.001)] and in the Aβ+ group [MMSE(β=-0.327, 95%CI -0.40-(-0.25)]; mPACC(β=-0.263, 95%CI -0.32-(-0.20); p <0.001)].

CONCLUSION: The longitudinal changes in plasma p-tau217 might serve as a surrogate marker for monitoring some aspects of disease progression during treatment trials.},
}

Humans
*Biomarkers/blood
Male
Female
*Amyloid beta-Peptides/blood
*tau Proteins/blood
Aged
Neurofilament Proteins/blood
*Cognitive Dysfunction/blood
Glial Fibrillary Acidic Protein/blood
*Alzheimer Disease/blood
Sweden
Peptide Fragments/blood
Longitudinal Studies
Aged, 80 and over
Middle Aged
Cohort Studies

@article {pmid41506295,
year = {2025},
author = {Condado, JG and Klinger, HM and Birkenbihl, C and Elorriaga, IT and Seto, M and Coughlan, GT and Properzi, MJ and Yang, HS and Erramuzpe, A and Rentz, DM and Schultz, AP and Chhatwal, JP and Johnson, KA and Cortes, JM and Sperling, RA and Hohman, TJ and Donohue, MC and Diez, I and Buckley, RF},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106989},
doi = {10.1002/alz70856_106989},
pmid = {41506295},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Biomarkers/metabolism ; Aged ; Magnetic Resonance Imaging ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism/pathology ; Positron-Emission Tomography ; *Brain/diagnostic imaging/pathology/metabolism ; *Cognitive Dysfunction/diagnostic imaging ; Longitudinal Studies ; *Aging/pathology ; Aged, 80 and over ; Cohort Studies ; Middle Aged ; Neuroimaging ; },
abstract = {BACKGROUND: BrainAge models estimate biological brain age based on neuroimaging data, providing a measure of brain health. This metric is particularly relevant in Alzheimer's disease (AD), where accelerated brain aging is exacerbated by β-amyloid (Aβ) and tau accumulation. We investigated the extent to which BrainAge moderates associations between AD biomarkers and longitudinal cognitive decline across two independent cohorts.

METHODS: We examined 1690 participants from A4/LEARN and 349 from HABS (Table 1). Using the Open-Source tool AgeML within each cohort, we built a BrainAge linear regressor model with 5-fold cross validation using MRI-T1 volumetric and FreeSurfer cortical thickness ROIs. We compared predicted ages with chronological age to create a BrainAgedelta. To avoid regressing out sex and APOEε4 variance, separate male/female models were built with data from APOEε4 non-carriers and applied to each cohort. We examined BrainAgedelta as a moderator of global neocortical Aβ-PET burden, temporal lobe Tau PET composite and p-tau217 associations with longitudinal PACC using linear mixed effects models. We adjusted for random intercepts and slopes, and baseline age, sex, years of education and APOEε4. In A4/LEARN we additionally adjusted for cumulative dose and treatment group using a spline model.

RESULTS: Higher levels of Aβ-PET, Tau-PET and p-tau217 at baseline was significantly correlated with higher BrainAgedelta (worse) (Figure 1). BrainAgedelta was directly associated with PACC trajectories in both cohorts. It also moderated the association between Aβ and Tau-PET and PACC trajectories such that higher BrainAgedelta was associated with faster cognitive decline with increasing levels of each biomarker. We found the same pattern of effects in p-tau217 limited only to the A4/LEARN sample but was trend-level in HABS (Figure 2).

CONCLUSIONS: BrainAgedelta is significantly associated with Aβ and tau burden and moderates their association with cognitive decline, supporting previous literature suggesting that BrainAge is a robust marker of brain health. Prioritizing individuals with worse BrainAge for clinical trials could not only effectively reduce screen fails (estimates forthcoming) but is a potentially feasible approach given that it can be calculated from a single T1-weighted MRI scan. These findings also highlight the importance of age-independent neurodegeneration patterns to contribute unique signal in models of brain health and pathological progression.},
}

Humans
Male
Female
Biomarkers/metabolism
Aged
Magnetic Resonance Imaging
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism/pathology
Positron-Emission Tomography
*Brain/diagnostic imaging/pathology/metabolism
*Cognitive Dysfunction/diagnostic imaging
Longitudinal Studies
*Aging/pathology
Aged, 80 and over
Cohort Studies
Middle Aged
Neuroimaging

@article {pmid41505775,
year = {2025},
author = {Saxena, S and Ye, Y and Devanarayan, V and Reyderman, L and Wildsmith, KR and Sachdev, P},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {Suppl 2},
pages = {e106893},
doi = {10.1002/alz70856_106893},
pmid = {41505775},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/genetics ; *RNA, Long Noncoding/cerebrospinal fluid/genetics ; *Biomarkers/cerebrospinal fluid ; Male ; Female ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; *Peptides/cerebrospinal fluid ; },
abstract = {BACKGROUND: Long non-coding RNAs (lncRNAs) play a significant role in the pathogenesis of Alzheimer's disease (AD). They modulate various cellular processes such as amyloid production, Tau hyperphosphorylation, neuroinflammation, and the impairment of mitochondrial and synaptic functions. Emerging studies have revealed that certain lncRNAs can encode small open reading frame-derived peptides. However, the identification and understanding of the role of lncRNA-encoded peptides in AD remain largely unexplored due to the inherent low abundance and small sizes of these peptides. Here, we leveraged the de novo peptide sequencing algorithm and a custom database to identify lncRNA-encoded peptides in cerebrospinal fluid (CSF) of demented subjects METHOD: We developed an innovative strategy to identify lncRNA-encoded peptides in biofluids. A custom database of hypothetical peptides was generated by six-frame translation of all lncRNAs from LNCipedia (www.lncipedia.org) and integrated to human SwissProt protein entries. MS data (PRIDE archive PXD016278) from CSF of demented subjects with (n = 29) or without (n = 31) amyloid positivity were analyzed. Peptide raw peak area intensities were quantile normalized and log2 transformed to reduce technical variation and ensure distribution symmetry. Differentially expressed peptides were identified via analysis of covariance after adjusting for age and gender, with the significant criteria based on 20% false discovery rate (FDR).

RESULT: The de novo-assisted search of MS spectra identified 32,191 peptides at 0.1% global peptide-level FDR. Mapping of de novo peptides to our custom database identified 99 lncRNA-encoded peptides in CSF of demented subjects. 7/99 significantly (q<0.2; Cohens >0.8) altered lncRNA-encoded peptides were linked to amyloid positivity. These peptides were translated from non-coding regions of six lncRNA genes involved in the cellular processes relevant to AD, including tau protein aggregation and glutamatergic synapse plasticity.

CONCLUSION: This is the first study identifying differentially regulated lncRNA-encoded peptides in the CSF of Ab+ (AD) and Ab- (non-AD) dementia. Further investigation of novel lncRNA-derived peptides lights a new beacon to explore their promising applications in AD diagnosis, staging, and future treatment strategies.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/genetics
*RNA, Long Noncoding/cerebrospinal fluid/genetics
*Biomarkers/cerebrospinal fluid
Male
Female
Aged
Amyloid beta-Peptides/cerebrospinal fluid
*Peptides/cerebrospinal fluid

@article {pmid41505707,
year = {2025},
author = {Anwar, M and Landry, B and Wang, W and Alhasan, K and Yang, H and Fraser, R},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105281},
doi = {10.1002/alz70856_105281},
pmid = {41505707},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; Male ; Female ; Aged ; Proteomics/methods ; *Metabolomics/methods ; Aged, 80 and over ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), a leading cause of dementia, poses a global health challenge as aging populations expand. Traditionally, practitioners rely on symptom-based identification, often miss the critical window for early intervention, limiting opportunities for improved clinical outcomes. Molecular You (MY) has developed an innovative, two-sided platform to address this gap. The platform i) quantifies 280 high-value plasma metabolites and proteins with absolute quantification and ii) through its algorithms ranks health risks and provides insights across more than 20 biological systems and pathways with an average predictive value of 88%. This study demonstrates the value of applying the MY platform in identifying AD risk and associated co-morbidities early, stratifying patients into endotype-specific mechanisms that inform customized care plans.

METHOD: Plasma samples from 74 patients, including 5 diagnosed with AD, were collected after an overnight fast, rapidly frozen, and shipped to MY for analysis. Each specimen underwent quantitative metabolomic (143 metabolites) and proteomic (140 proteins) assays using well-established LC-MS/MS methods. The resulting data were processed through the MY platform to identify health risks and map key biological pathways.

RESULT: Four of the five patients diagnosed with AD were confirmed, while one patient's profile was more aligned with vascular dementia. Additionally, 36 patients were identified at moderate to high risk for AD. Analysis of the biological pathways revealed several distinct endotypes for AD risk: dyslipidemia/ abnormal lipid metabolism, metabolic aberrations, inflammation and oxidative stress driving neuroinflammation and neurodegeneration, and neurotransmitter dysfunction leading to excitotoxicity and synaptic dysfunction. Several co-morbidities were identified in the population, including metabolic health issues such as diabetes, kidney health, liver health, immune health, cardiovascular disease, and inflammatory bowel disease. Personalized care plans were developed based on these findings, incorporating targeted dietary, lifestyle, and clinical interventions.

CONCLUSION: The MY platform demonstrates the feasibility of multi-omic analysis of blood to enhance the early detection of AD before clinical symptoms manifest, identify emerging co-morbidities, stratify patients into AD endotypes enabling precision preventative and personalized care. By monitoring patients longitudinally using the MY platform it will be possible to objectively quantify treatment efficacy, safety and overall patient outcomes.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/blood/diagnosis
Male
Female
Aged
Proteomics/methods
*Metabolomics/methods
Aged, 80 and over

@article {pmid41505448,
year = {2025},
author = {Steward, A and Dewenter, A and Roemer-Cassiano, S and Biel, D and Zhu, Z and Frontzkowski, L and Hirsch, F and Klonowksi, M and Gnörich, J and Dehsarvi, A and Brendel, M and Franzmeier, N},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105476},
doi = {10.1002/alz70856_105476},
pmid = {41505448},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/cerebrospinal fluid/metabolism/blood ; *Alzheimer Disease/genetics/diagnostic imaging/cerebrospinal fluid/metabolism ; Biomarkers/cerebrospinal fluid/blood ; Female ; Male ; *Apolipoprotein E4/genetics ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Aged ; Positron-Emission Tomography ; Aged, 80 and over ; Cross-Sectional Studies ; Alleles ; Brain/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: Understanding factors influencing Alzheimer's disease (AD) progression is crucial for optimising treatment timing and targets. A major genetic risk factor, the Apolipoprotein E ε4 allele (ApoE4), is associated with earlier tau pathology accumulation and spread at lower amyloid-beta (Aβ) levels (Steward, JAMA Neurol, 2023). However, the mechanisms underlying this association remain unclear (Figure 1A). Therefore, we assessed how ApoE4 accelerates Aβ-related tau aggregation. Specifically, we investigated whether ApoE4 promotes Aβ-driven secretion of phospho tau (p-tau) or ptau dependent tau aggregation, and determined whether ApoE4 promotes tau pathology in an allele dose-dependent manner.

METHOD: We analysed data from APOE-genotyped AD-spectrum participants in the ADNI (n = 201) and A4 cohorts (n = 200), integrating cross-sectional fluid biomarker measures (plasma ptau217, CSF ptau181) and longitudinal Flortaucipir tau-PET and Florbetaben/Florbetapir amyloid-PET. Using linear regression, we assessed whether the interaction between amyloid-PET and ApoE4 allele dosage influences plasma ptau217, and replicated this analysis with CSF ptau181 in an ADNI subset (n = 115). Secondly, to investigate whether ApoE4 enhances tau fibrilisation and spread, we calculated annual tau-PET SUVR accumulation rates across a connectivity-based tau spreading stages, using our prior methodology (e.g. Franzmeier, Sci Adv, 2020). Linear regressions tested the interaction between ptau217 (or CSF ptau181) and ApoE4 allele count on connectivity-mediated tau-PET accumulation in four connectivity stages that capture progressive tau spread.

RESULT: ApoE4 allele dosage did not moderate the relationship between amyloid-PET and plasma ptau217 in either sample (Figure 1B, ADNI: β=0.13, p = 0.32; A4: β=-0.20, p = 0.17) nor between amyloid-PET and CSF ptau181 in ADNI subsample (Figure 1B, b=-.16, p = 0.42). However, a significant ApoE4 allele dose effect was observed in moderating the relationship between plasma ptau217 and tau-PET accumulation across connectivity stages independent of amyloid burden (Figure 1C, ADNI: Q1-4 mean β=0.44, Q1-4 p <0.001; A4: Q1-4 mean β = 0.56, Q1,2,4 p <0.001, Q3 p <0.05), with the strongest effect in individuals carrying two ApoE4 alleles.

CONCLUSION: ApoE4 exerts an allele dose-dependent effect on ptau induced tau aggregation, driving accelerated tau spreading at lower Aβ levels. This suggests that attenuating soluble ptau increases in ApoE4 carriers may mitigate downstream tau fibrilisation and delay dementia onset, highlighting the potential of personalised therapeutic approaches.},
}

Humans
*tau Proteins/cerebrospinal fluid/metabolism/blood
*Alzheimer Disease/genetics/diagnostic imaging/cerebrospinal fluid/metabolism
Biomarkers/cerebrospinal fluid/blood
Female
Male
*Apolipoprotein E4/genetics
Amyloid beta-Peptides/metabolism/cerebrospinal fluid
Aged
Positron-Emission Tomography
Aged, 80 and over
Cross-Sectional Studies
Alleles
Brain/diagnostic imaging/metabolism

@article {pmid41505228,
year = {2026},
author = {Head, E and Cohen, A and Fortea, J and McGlinchey, E},
title = {Novel insights into Alzheimer's disease through the study of individuals with Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71074},
doi = {10.1002/alz.71074},
pmid = {41505228},
issn = {1552-5279},
support = {U19AG068054//NIH/NIA/ ; U19AG068054//NIH/NIA/ ; P30AG066519//NIH/NIA/ ; RF1AG079519//NIH/NIA/ ; U19AG068054//NIH/NIA/ ; P30AG066519//NIH/NIA/ ; RF1AG079519//NIH/NIA/ ; R01AG056850//NIH/NIA/ ; R21AG056974//NIH/NIA/ ; R01AG061566//NIH/NIA/ ; 1R01AG081394//NIH/NIA/ ; R61AG066543//NIH/NIA/ ; //Fondo de Investigaciones Sanitario/ ; INT21/00073//Carlos III Health Institute/ ; PI20/01473//Carlos III Health Institute/ ; PI23/01786//Carlos III Health Institute/ ; //Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Program 1/ ; //Fondo Europeo de Desarrollo Regional/ ; SLT006/17/00119//Department de Salut de la Generalitat de Catalunya/ ; //Fundación/ ; IIBSP-DOW-2020-151//Tatiana Pérez de Guzmán el Bueno/ ; H2020-SC1-BHC-2018-2020//Horizon 2020-Research and Innovation Framework Programme/ ; HPE-ADRD 24HPE1284307//Alzheimer Association/ ; },
}

@article {pmid41505225,
year = {2025},
author = {Ramirez-Galvan, FA and Jimenez-Galaviz, DA and Padilla-Mendoza, JR and Jijon-Lorenzo, R and Silva-Lucero, MD and Cardenas-Aguayo, MD},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105315},
doi = {10.1002/alz70856_105315},
pmid = {41505225},
issn = {1552-5279},
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/blood/complications ; Biomarkers/blood ; Male ; *Cognitive Dysfunction/blood/metabolism ; Female ; Autophagy/drug effects ; Aged ; Metformin/pharmacology ; Glycated Hemoglobin/metabolism ; Middle Aged ; Hypoglycemic Agents/pharmacology ; },
abstract = {BACKGROUND: Type 2 Diabetes (T2D) is highly prevalent in Latin America, particularly in Mexico, with 15.6% of the population affected (ENSANUT 2020, Montoya 2023). T2D increases the risk of complications: hypertension and dementia. Mild Cognitive Impairment (MCI) precedes Alzheimer's dementia, the most common type. Metformin, the primary treatment for T2D, enhances autophagy, a cellular process for recycling primary components. Autophagy impairment is linked to dementia (Nixon 2024). This study utilizes human olfactory neuroepithelial precursor cells (hONE-NPCs) as a model for neurodegeneration. Olfactory dysfunction is an early indicator of dementia, suggesting that alterations in hONE-NPCs may reflect early stages of the disease.

METHOD: This study included four groups: healthy controls, individuals with cognitive impairment, those with T2D, and with T2D and cognitive impairment (T2D-MCI). hONE NPCs were isolated from each participant and characterized using Western Blotting and immunocytofluorescence. Blood samples were collected for HbA1c and protein samples for autophagy markers. Participants underwent a MoCA Test by a certified applicator (MXRAMFR710802563-01), a medical interview to assess metformin treatment history, and an olfactory test. hONE-NPCs were treated with or without metformin for 24 hours. Protein samples were collected for Western Blotting analysis in three groups in vitro: Diabetes+MCI+Metformin, Diabetes-MCI-Metformin, and Control+Metformin.

RESULT: Culture cells hONE-NPCs from Diabetes+MCI and Pre-Diabetic+MCI from patients that had been treated with metformin and their cells were treated with metformin show an impairment in the autophagy flux since p62 was elevated and LC3-II was downregulated. Conversely, culture cells from control individuals who had never been treated with metformin responded to metformin in vitro treatment with an increase in autophagy flux, showing p62 reduction and an increase in LC3-II.

CONCLUSION: Our results suggest a preconditioning effect of hONE-NPCs from patients receiving metformin treatment on their response to this drug in vitro. Cells from patients who were prescribed metformin show an impairment in the autophagy flux; however, culture hONE.NPCs cells from control individuals who had never been treated with metformin responded to metformin in vitro treatment with an increase in autophagy flux. This finding may have clinical implications in the long-term effects of metformin treatment in peripheral cells as a systemic effect.},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy/blood/complications
Biomarkers/blood
Male
*Cognitive Dysfunction/blood/metabolism
Female
Autophagy/drug effects
Aged
Metformin/pharmacology
Glycated Hemoglobin/metabolism
Middle Aged
Hypoglycemic Agents/pharmacology

@article {pmid41505203,
year = {2026},
author = {Lyketsos, CG and Peters, ME},
title = {Neuropsychiatric symptoms in Alzheimer's disease: Past, present, and future.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71077},
doi = {10.1002/alz.71077},
pmid = {41505203},
issn = {1552-5279},
support = {P30AG066507//Johns Hopkins Alzheimer's Disease Research Center/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/complications ; *Cognitive Dysfunction/psychology ; Disease Progression ; *Depression/etiology ; },
abstract = {Noncognitive neuropsychiatric symptoms (NPS; e.g., depression, agitation) are nearly universal throughout the course of Alzheimer's disease (AD), cause significant adverse impact to patients and caregivers, and are associated with more rapid progression to severe dementia. Although the importance and presence of NPS was recognized by Dr. Alois Alzheimer himself, it was a series of research roundtables in the 2010s that propelled the understanding and treatment of NPS in AD forward. The mild behavioral impairment (MBI) construct was developed as a complementary behavioral analogue to mild cognitive impairment, solidifying the importance of NPS prior to dementia onset. Neurobiological underpinnings of NPS are being studied and the NPS treatment pipeline includes novel therapeutics, repurposing of existing pharmaceuticals, and non-pharmacologic interventions. The Alzheimer's Disease Research Centers and The National Alzheimer's Coordinating Center, being recognized in this special issue, have played a pivotal role in the recognition and study of NPS in AD. HIGHLIGHTS: Noncognitive neuropsychiatric symptoms (NPS) are nearly universal throughout the course of Alzheimer's disease (AD), cause significant adverse impact to patients and caregivers, and are associated with more rapid progression to severe dementia. A series of research roundtables in the last decade and a half have propelled the understanding and treatment of NPS in AD forward. The mild behavioral impairment (MBI) construct was developed as a complementary behavioral analogue to mild cognitive impairment, solidifying the importance of NPS prior to dementia onset. Neurobiological underpinnings of NPS are being studied and the treatment pipeline includes novel therapeutics, repurposing of pharmaceuticals, and non-pharmacologic interventions. The Alzheimer's Disease Research Centers and The National Alzheimer's Coordinating Center have played a pivotal role in the recognition and study of NPS in AD.},
}

Humans
*Alzheimer Disease/psychology/complications
*Cognitive Dysfunction/psychology
Disease Progression
*Depression/etiology

@article {pmid41505171,
year = {2025},
author = {Coughlan, GT and Klinger, HM and Seto, M and Birkenbihl, C and Li, A and Farrell, ME and Thibault, EG and Properzi, MJ and Schultz, AP and Townsend, DL and Langford, O and Chhatwal, JP and Yang, HS and Raman, R and Donohue, MC and Johnson, KA and Sperling, RA and Buckley, RF},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106874},
doi = {10.1002/alz70856_106874},
pmid = {41505171},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/blood/metabolism ; Male ; Female ; *Biomarkers/blood ; Aged ; Positron-Emission Tomography ; *Amyloid beta-Peptides/blood/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Longitudinal Studies ; *Brain/metabolism/diagnostic imaging ; Middle Aged ; Peptide Fragments/blood ; Aged, 80 and over ; Phosphorylation ; },
abstract = {BACKGROUND: The pathophysiological cascade of Alzheimer's Disease(AD) is characterized by amyloid-β(Aβ) related secretion of soluble phosphorylated tau (p-tau), followed by aggregation of tau tangles and subsequent cognitive decline. Previous literature suggests that tau proliferation is more aggressive at younger ages, but the extent to which this is true and can be detected by plasma markers remains unclear. We examined whether age interacts with plasma p-tau217 and p-tau217/Aβ42 and to predict rates of regional tau-PET accumulation in baseline clinical normal adults.

METHOD: Participants were 578 clinically normal individuals (mean age 72.2; 295 APOEε4-carriers [56%]; mean years of education 16.3) with baseline plasma p-tau217 and longitudinal tau-PET from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study as well as the Alzheimer's Disease Neuroimaging Initiative. Medial temporal lobe (amygdala, parahippocampal gyrus, entorhinal cortex) and neocortical (inferior parietal, fusiform, inferior temporal) tau composites were chosen as longitudinal tau-PET outcomes. The average tau-PET follow-up time was 3.5 years (SD=1.6 years, range=1.3-7.1 years). Random-effects regression estimated the interaction between baseline age and baseline p-tau217 longitudinal tau composites, adjusting for sex and years of education (including participant-specific intercepts and slopes).

RESULT: In A4/LEARN, age moderated the association between plasma p-tau217 and neocortical tau accumulation (β=-0.06, =-0.09 - -0.04, p <0.001; Figure 1A), such that the effects of elevated p-tau217 on tau were stronger at younger ages. Similarly in ADNI, age moderated the association between p-tau217/Aβ42 and neocortical tau accumulation (β=-0.12, =-0.18 - -0.06, p <0.001;Figure 1B, such that the effects of elevated p-tau217/Aβ42 on tau accumulation were stronger at younger ages. The raw tau trajectories for one neocortical region as a function of age and p-tau217 is illustrated in Figure 1C. In Post-hoc analysis covarying APOEε4 status, the interactive effects of age and p-tau217 remained significant.

CONCLUSION: There is evidence for more aggressive tau-related processes in younger individuals. These findings highlight the critical need for early identification and enrollment in AD clinical trials, potentially using plasma biomarkers in primary care and secondary care.},
}

Humans
*tau Proteins/blood/metabolism
Male
Female
*Biomarkers/blood
Aged
Positron-Emission Tomography
*Amyloid beta-Peptides/blood/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Longitudinal Studies
*Brain/metabolism/diagnostic imaging
Middle Aged
Peptide Fragments/blood
Aged, 80 and over
Phosphorylation

@article {pmid41504713,
year = {2025},
author = {Marcatti, M and Fracassi, A and Zhang, W and Kayed, R and Taglialatela, G},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e106869},
doi = {10.1002/alz70856_106869},
pmid = {41504713},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; *tau Proteins/blood/metabolism ; Male ; *Cognitive Dysfunction/blood/diagnosis ; Female ; Amyloid beta-Peptides/blood ; Aged ; *Extracellular Vesicles/metabolism ; *Brain/metabolism/pathology ; Aged, 80 and over ; Longitudinal Studies ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most common forms of dementia worldwide, making the identification of predictive biomarkers critical for early diagnosis and treatment during the preclinical stage. Recent studies have focused on blood-based biomarkers, particularly plasma brain-derived extracellular vesicles (pl-BDEVs), to detect central nervous system (CNS) alterations. While blood biomarkers like amyloid proteins (Aβ42/Aβ40), tau, and phosphorylated tau show diagnostic promise, identifying predictive biomarkers remains essential. Blood total-tau, originating from non-brain sources, highlights the need to analyze brain-derived tau (BDT) in pl-BDEVs as a more specific biomarker for AD and other neurodegenerative diseases. Longitudinal studies offer great potential for detecting preclinical biomarker patterns in at-risk individuals, yet little attention has been given to oligomers, the most toxic species in AD METHOD: In this study, we enriched pl-BDEVs from CNS cell types from plasma samples longitudinally collected from participants enrolled in the Texas Alzheimer's Research and Care Consortium (TARCC), who were initially cognitively normal or displayed mild cognitive impairment (MCI), and later either progressed to AD (termed "converters") or remained cognitively normal/MCI (termed "non-converters"). We evaluated the isolated pl-BDEVs by nanoparticle tracking analysis (size, number, and distribution), western blot (expression of extracellular vesicles markers: CD63, CD9, CD81), and electron microscopy. We immunoprecipitated brain-derived tau oligomers (BDTOs) from pl-BDEVs and characterized them by western blot, proteinase K (PK) digestion, seeding assay, and atomic force microscopy (AFM). Additionally, we treated SH-SY5Y neuroblastoma cells and human synaptosomes isolated from cortex of control samples with these BDTOs and assessed their cytotoxicity and synaptotoxicity, respectively.

RESULT: We demonstrated the successful isolation of pl-BDEVs from plasma samples and the detection of BDTOs within these pl-BDEVs. We identified distinct PK digestion patterns, morphology, and toxicity between BDTOs from converters and non-converters. Additionally, our data revealed different distribution of BDTOs in the pl-BDEVs isolated from the two groups. These findings suggest the presence of two different BDTO strains for converters and non-converters.

CONCLUSION: This study addresses the need for predictive AD biomarkers by analyzing previously unexplored BDTO conformers in pl-BDEVs. Discovering distinct BDTOs in peripheral brain derived extracellular vesicles could enable preclinical forecasting and advance early-stage AD treatments.},
}

Humans
*Biomarkers/blood
*Alzheimer Disease/blood/diagnosis
*tau Proteins/blood/metabolism
Male
*Cognitive Dysfunction/blood/diagnosis
Female
Amyloid beta-Peptides/blood
Aged
*Extracellular Vesicles/metabolism
*Brain/metabolism/pathology
Aged, 80 and over
Longitudinal Studies

@article {pmid41502736,
year = {2025},
author = {Biswal, B and Pattnaik, S and Satapathy, BS and Maharana, L},
title = {Luliconazole-Loaded Nanoliposomes as a Repurposing Strategy to Combat Memory Dysfunction in LPS-Induced Alzheimer's Rats.},
journal = {ACS omega},
volume = {10},
number = {48},
pages = {59655-59674},
pmid = {41502736},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder with no definitive cure. Out of several proposed pathophysiology, microbial infection has recently been identified as one of the key pathogenic contributors for the development and progression of AD. In this context, the present study aims at a repurposing strategy through luliconazole (a potent imidazole derivative)-loaded optimized nanoliposomal carriers to treat AD. Optimized luliconazole-loaded nanoliposomes (LuNLs) were developed by the conventional thin-film hydration method followed by characterization in terms of FESEM, AFM, zeta potential, average size, loading %, and drug release (in vitro). The in vivo effectiveness of the LuNLs was investigated in LPS-induced AD rats. Molecular docking and simulation analysis demonstrated a favorable docking score between luliconazole and selected AD proteins. Spherical, nanosized (52.42 nm), negatively charged (-29.9 mV) LuNLs were reported showing a sustained drug release up to 24 h. An in vivo behavioral study depicted improved cognitive behavior in the LuNLs-treated group as compared to control groups. In vivo antioxidant activity in terms of SOD, MDA, and GSH inhibition by LuNLs was found comparable to that of standard formulation-treated groups, depicting the neuroprotective behavior of LuNLs. The histopathological observation of brain tissue in the LuNLs/control group further substantiated the in vivo behavioral study data. Based on the reports, luliconazole may be used as a viable, efficacious alternative for the treatment of AD, though further preclinical studies are highly warranted.},
}

@article {pmid41502722,
year = {2025},
author = {Wu, H and Huang, N and Wang, K and Mi, J and Liu, Z and Wang, J and Sang, Z and Tan, Z},
title = {Development of Novel 3‑Phenylpropanamide Derivatives as BChE Inhibitors for the Treatment of Alzheimer's Disease.},
journal = {ACS omega},
volume = {10},
number = {48},
pages = {59522-59534},
pmid = {41502722},
issn = {2470-1343},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative degenerative disorder among the elderly, featured by progressive cognitive decline and memory impairment. Due to its complex pathogenesis, there is still no effective therapeutic drug to date. Recently, selective BChE inhibition has been regarded as a potent approach for treating AD. In this work, we conducted structural optimization and structure-activity relationship studies on the previously obtained lead compound EMC-4f, and obtained the potential selective BChE inhibitor 12a (eqBChE, IC50 = 1.3 μM; huBChE, IC50 = 0.95 μM). The in vitro results exhibited that 12a showed good BBB permeability. Moreover, 12a demonstrated significant neuroprotective effects on l-Glu/Aβ25-35-induced HT22 cells injury. Further, the in vivo tests suggested that 12a remarkably alleviated mice cognitive impairment induced by scopolamine. Therefore, these data present that 12a is a promising BChE inhibitor against AD.},
}

@article {pmid41502346,
year = {2026},
author = {Chang, YY and Zheng, XH and Wang, MW and Zhang, QW and Gao, YT and Wang, YN and Sun, YT and Fan, HH and Li, X and Du, LD and Xie, XM and Pang, XB},
title = {Morroniside Modulates Microglia Polarization via the CX3CL1/CX3CR1/PU.1 Axis in ApoE4 Transgenic Mice.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70177},
pmid = {41502346},
issn = {1099-1573},
support = {251111313400//Key R&D Program of Henan Province/ ; 252300421379//Natural Science Foundation of Henan/ ; 25B350004//Key Scientific Research Projects of Henan Higher Education Institutions/ ; 82501727//Natural Science Foundation of China/ ; 22508091//Natural Science Foundation of China/ ; },
abstract = {Microglia monitor disease stimulation, neuronal apoptosis, and neural repair, and their overactivation-induced inflammation plays a key role in the pathogenesis of Alzheimer's disease (AD). Morroniside (Mor), an iridoid glycoside compound in Cornus officinalis, is one of the effective active components. The effects of Mor on antioxidant stress, antiapoptosis, and nerve repair function have been widely studied, but the mechanism of Mor in AD treatment remains unclear. To study the neuroprotective effects of Mor and elucidate the molecular mechanisms underlying its improvement of AD symptoms, we used ApoE4 transgenic mice and ApoE4-transfected BV2 cells as models of AD, focusing on microglia phenotype, function, and neuroinflammation. The 10-month-old mice were randomly divided into the ApoE3 control group (ApoE3 + Veh), the ApoE4 model group (ApoE4 + Veh), and the ApoE4 + Mor 10, 20, and 40 mg/kg groups as in vivo models. The in vitro BV2-ApoE model was constructed via lentiviral transfection. The effects of Mor on cognitive function of AD models were assessed through behavioral tests, western blot, immunofluorescence staining, and ELISA to measure changes of related pathological and inflammatory factors. Mor improved the cognitive function of ApoE4 transgenic mice by reducing Aβ plaques in the brain, improving the structural lesions of hippocampal neurons, and increasing synaptic plasticity in the brain of AD mice. In addition, Mor promoted the transformation of microglia from the M1 to the M2 phenotype, inhibited the activation of the CX3CR1/PU.1 signaling axis, and alleviated the dysfunction of microglia both in vitro and in vivo. CX3CR1 siRNA and PU.1 siRNA were used further to verify the regulatory effect of Mor on microglia phenotype. Our findings indicate that Mor can inhibit neuroinflammation, reduce Aβ accumulation, and improve synaptic damage in ApoE4 mice via the CX3CL1/CX3CR1/PU.1 pathway regulating the phenotype and function of microglia. This study provides a new therapeutic candidate for the prevention and treatment of AD.},
}

@article {pmid41502301,
year = {2026},
author = {Abhyankar, SD and Xiao, Y and Mahajan, N and Luo, Q and Cummins, TR and Oblak, AL and Lamb, BT and Corson, TW and Bhatwadekar, AD},
title = {Müller Glial Kir4.1 Channel Dysfunction in APOE4-KI Model of Alzheimer's Disease.},
journal = {Glia},
volume = {74},
number = {3},
pages = {e70119},
doi = {10.1002/glia.70119},
pmid = {41502301},
issn = {1098-1136},
support = {R01EY027779-S1/EY/NEI NIH HHS/United States ; R01EY032080/EY/NEI NIH HHS/United States ; //Research to Prevent Blindness, Unrestricted Grant/ ; DK064466/DK/NIDDK NIH HHS/United States ; G20240315-8762//Sigma Xi Grants in Aid of Research/ ; //NIH T32, Peter J. Roach Award, Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine/ ; },
mesh = {Animals ; *Potassium Channels, Inwardly Rectifying/metabolism/genetics ; *Alzheimer Disease/metabolism/genetics/pathology ; *Ependymoglial Cells/metabolism/pathology/drug effects ; *Apolipoprotein E4/genetics/metabolism ; Kcnj10 Channel ; Disease Models, Animal ; Mice, Transgenic ; Rats ; Mice ; Mitochondria/metabolism ; Oxidative Stress/physiology ; Retina/metabolism/pathology ; Mice, Inbred C57BL ; },
abstract = {Alzheimer's disease (AD), particularly late-onset AD (LOAD), affects millions worldwide, with the apolipoprotein ε4 (APOE4) allele being a significant genetic risk factor. Retinal abnormalities are a hallmark of LOAD, and our recent study demonstrated significant age-related retinal impairments in APOE4-knock-in (KI) mice, highlighting that retinal impairments occur before the onset of cognitive decline in these mice. Müller cells (MCs), key retinal glia, are vital for retinal health, and their dysfunction may contribute to retinal impairments seen in AD. MCs maintain potassium balance via specialized inwardly rectifying K[+] channels 4.1 (Kir4.1). This study posits that Kir4.1 channels will be impaired in APOE4-KI, resulting in MC dysfunction. Additionally, we demonstrate that MC dysfunction in APOE4-KI stems from alterations in mitochondrial dynamics and oxidative stress. Kir4.1 expression and function were studied using immunofluorescence and through the whole-cell voltage clamp, respectively. In parallel, rat Müller cells (rMC-1) were used to create an in vitro model for further mechanistic studies. MitoQ was used to evaluate its potential to mitigate APOE4-induced deficits. APOE4 retinas and APOE4-transfected rMC-1 significantly reduced Kir4.1 expression, K+ buffering capacity, and increased mitochondrial damage. APOE4-transfected rMC-1 showed reduced mitochondrial membrane potential (ΔΨm) and increased mitochondrial reactive oxygen species (ROS). MitoQ treatment significantly reduced mitochondrial ROS and restored Kir4.1 expression in APOE4-expressing cells. Our results demonstrate that APOE4 causes mitochondrial dysfunction and MC impairment, which may contribute to retinal pathology in AD. MitoQ restored mitochondrial health and Kir4.1 expression in APOE4-expressing rMC-1, suggesting targeting mitochondria may offer a promising therapeutic strategy for AD.},
}

Animals
*Potassium Channels, Inwardly Rectifying/metabolism/genetics
*Alzheimer Disease/metabolism/genetics/pathology
*Ependymoglial Cells/metabolism/pathology/drug effects
*Apolipoprotein E4/genetics/metabolism
Kcnj10 Channel
Disease Models, Animal
Mice, Transgenic
Rats
Mice
Mitochondria/metabolism
Oxidative Stress/physiology
Retina/metabolism/pathology
Mice, Inbred C57BL

@article {pmid41501928,
year = {2026},
author = {Li, E and Song, F and Coppola, Q and Yack, L and Le, M and Javed, S and Pandher, N and Prufer, I and Mayzel, O and Heuer, HH and Koestler, M and Miller, BL and Boxer, AL and Vandevrede, L and Grinberg, LT and Walsh, CM and Neylan, TC},
title = {Treatment of Disturbed Sleep in Progressive Supranuclear Palsy: a randomized, remote, double-blinded, 6-week cross-over design study protocol comparing zolpidem, suvorexant, and placebo.},
journal = {Trials},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13063-025-09382-9},
pmid = {41501928},
issn = {1745-6215},
support = {A130340//Rainwater Charitable Foundation/ ; },
abstract = {BACKGROUND: Prior research identified profound sleep disruption in progressive supranuclear palsy (PSP). The hypothalamus and brainstem, areas that help regulate sleep/wake patterns, are among the earliest affected brain regions in PSP disease progression. Comparing polysomnography and quantitative-neuropathology metrics, we identified relative sparing of wake-promoting nuclei in PSP compared to Alzheimer's disease, though PSP had more disrupted sleep. It led to the hypothesis that PSP patients have hyperinsomnia (or hyposomnia, little sleep) due to degeneration of sleep nuclei with a preservation of sleep neurons, causing a system unbalance. A higher neuronal count of wake-promoting nuclei was associated with greater nocturnal wake, regardless of disease. Specifically, orexinergic wake-promoting neurons in the lateral hypothalamus, previously described as the sleep-on/off switch, are relatively spared in PSP. Thus, we hypothesized that an orexinergic antagonist may be more effective in treating sleep/wake issues in PSP than other hypnotic medications. This study protocol was established to test the safety and efficacy of an orexinergic antagonist (suvorexant) targeting the wake-promoting system and contrasts it with a GABAergic receptor agonist (zolpidem) targeting sleep-promoting systems and placebo.

METHODS: This is a remote clinical trial, designed as a double-blind, cross-over, within-subject 6-week trial, with 3 one-week-long conditions, separated by 1-week washout periods. The order of the 3 regimens is randomized and counterbalanced: placebo (microcrystalline cellulose), 15 mg/day suvorexant, 5 mg/day zolpidem. Participants are recruited from doctor and study referrals, registries, and support groups. Once onboarded, the trial coordinator maintains communication with the participant/caregiver throughout the 6 weeks. Assessments include neurological interviews, cognitive testing, and subjective questionnaire packets. Sleep and circadian rhythms are assessed through ambulatory EEG and actigraphy monitoring devices worn by the participant throughout the trial.

DISCUSSION: The study design aims to reduce participant and caregiver burden, while improving accessibility to such a study. Administering a remote clinical trial for a rare disease, however, creates unique issues that would otherwise be absent from in-person studies. Particularly, a symptom rather than disease-modifying trial is challenging to recruit for when potential disease-modifying therapeutics are available. Needing to coordinate with non-associated medical offices to attain medical records or prescriptions can cause frustrations for the potential participant, medical office, and study team. In recruitment, onboarding, and trial maintenance, this study design relies on consistent communication to support participant enrollment and satisfaction.

TRIAL REGISTRATION: Treatment of Disturbed Sleep in Progressive Supranuclear Palsy (PSP); NCT04014389. Registered on June 2, 2019.},
}

@article {pmid41469664,
year = {2025},
author = {Yu, X and Xiao, H and Bao, S and Dong, Y and Dong, Z and Zhao, J and Wang, G and Meng, X and Wang, F},
title = {Cigarette smoke-induced lung-brain barrier dysfunction drives neurocognitive impairment via inflammatory spill-over.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {10},
pmid = {41469664},
issn = {1742-2094},
support = {2024CX129//the Graduate Innovation Fund of Jilin University/ ; Not applicable//the Medical Basic Research Innovation Center of Airway Disease in North China/ ; Not applicable//Key Laboratory of Pathobiology/ ; 20200601011JC//Key Laboratory of Precision Infectious Diseases, Jilin Province/ ; 2022C036//Engineering Laboratory for Precision Prevention and Treatment of Common Diseases, Jilin Province/ ; 20230204055YY//Department of Science and Technology of Jilin Province: Key Scientific and Technological Research and Development Projects/ ; },
abstract = {BACKGROUND: Although the association between cigarette smoke (CS)-induced chronic obstructive pulmonary disease (COPD) and neurocognitive disorders is recognized, the underlying mechanisms remain unclear. To date, no studies have linked alterations in lung and brain barrier permeability to the “spill-over” of inflammatory factors in CS induced COPD-related neurocognitive disorders (COPD-NCDs).

METHODS: Using GWAS data, a two-sample Mendelian randomization (MR) analysis was conducted to explore the genetic associations between COPD and neurocognitive disorders (dementia, Alzheimer’s disease, etc.). A BALB/c female mouse model with CS exposure (9 cigarettes/day × 24 weeks) was established. Cognitive functions were evaluated using open field tests, novel object recognition tests, and Morris water maze tests. Histopathological changes were observed by HE and Masson staining. Cellular and molecular profiles in brain tissues were analyzed by single-cell RNA sequencing. Levels of inflammatory factors were detected by ELISA. Barrier permeability changes in the lungs and brain were assessed by using Evans Blue staining. Tight junction proteins in lung and brain tissues were measured by immunofluorescence and Western blotting.

RESULTS: MR analysis revealed causal associations between COPD and Alzheimer’s disease, dementia, depression, anxiety, and Parkinson’s disease. CS-exposed mice exhibited COPD phenotypes (emphysema, reduced lung function) and cognitive impairments (memory deficits, anxiety-like behaviors). Activation of microglia/astrocytes and decreased neuronal/synaptic marker expression were observed in the hippocampus. Increased leakage of Evans blue staining in the lungs and brain, along with downregulated expression of tight junction proteins (Occludin, Claudin1, ZO-1), indicated increased blood-brain barrier (BBB) permeability. Elevated levels of inflammatory factors (IL-1β, IL-6, TNF-α) were detected in lung tissues, brain tissues and serum.

CONCLUSIONS: CS exposure disrupts lung barrier function, leading to the “spill-over” of inflammatory factors to the brain via the lung-brain axis. This increases BBB permeability, triggering neuroinflammation, impairing hippocampal neuronal and synaptic function, and ultimately causing neurocognitive disorders. This study elucidates a novel mechanism of COPD-NCDs, which may provide new targets for the treatment of COPD-NCDs.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03629-7.},
}

@article {pmid41501420,
year = {2026},
author = {Wang, XY and Zhou, WS and Gaur, U and Zhen, XC and Zheng, WH},
title = {Sigma-1 receptor positive allosteric modulator promotes neuronal survival and improves cognitive deficits in AD mice via sigma-1 receptor/ERK pathway.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {41501420},
issn = {1745-7254},
abstract = {The sigma-1 receptor is an important new therapeutic drug target for Alzheimer's disease (AD). Here, we reported that SOMCL-668, a novel selective and potent sigma-1 receptor allosteric modulator, is neuroprotective in AD both in vitro and in vivo. SOMCL-668 promoted PC12 cells against Aβ-induced intracellular reactive oxygen species (ROS) accumulation, mitochondrial membrane potential hyperpolarization and neuronal apoptosis. Similar results were obtained in SH-SY5Y and primary cortical culture neurons. The mechanistic study showed that SOMCL-668 stimulated the phosphorylation of ERK and CREB, while pharmacological inhibition or knockout of ERK via CRISPR-Cas9 attenuated its protective effects. Further studies with the sigma-1 receptor agonists/antagonists and knockout of sigma-1 receptor via CRISPR-Cas9 indicated that the sigma-1 receptor is essential for the effect of SOMCL-668. In 3xTg-AD mice, SOMCL-668 improved the learning and memory deficits, inhibited neuronal apoptosis and oxidative stress, reduced Aβ deposition and tau protein phosphorylation via ERK/CREB pathway. Moreover, pretreatment with sigma-1 receptor antagonist BD1047 blocked the effect of SOMCL-668. These results demonstrated that SOMCL-668 provides neuroprotection in AD and its effect is mediated by the sigma-1 receptor/ERK/CREB pathway. Our findings support that SOMCL-668 can be utilized as a potential drug for the prevention and treatment of Alzheimer's disease.},
}

@article {pmid41500848,
year = {2025},
author = {Prabha, PK and Jain, A and Dadoo, N and Charan, S and Medhi, B and Prakash, A},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105361},
doi = {10.1002/alz70856_105361},
pmid = {41500848},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnosis ; *Biomarkers/blood ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Cholesterol/metabolism ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition marked by memory loss, cognitive decline, and eventually motor and behavioural dysfunction. Most AD drug trials have failed due to the lack of early intervention, which is crucial for treatment effectiveness. Though early diagnosis remains challenging owing to blood-brain barrier, blood-based biomarkers are being explored due to their non-invasive nature. Genes involved in cholesterol and lipid metabolism, such as APOE, APOJ, ABCA7, and SORL1, have also been observed to increase AD risk.

METHODS: Clinical studies of polymorphisms in cholesterol homeostasis pathway involving participants clinically diagnosed with Alzheimer's Disease of any form as per set criteria of diagnosis for AD were included after comprehensive search across PubMed, Embase, Scopus and Web of Science. Independent reviewers extracted data from the included studies which included information like general information, participants, study methods, polymorphisms studied, outcomes, results, conclusion, etc. Any discrepancies or doubts was resolved by a third reviewer.

RESULT: A total of 1870 studies were identified based on the designed search strategy, which reduced to 216 after removal of duplicates, with 45 studies considered suitable for the final meta-analyses. The risk of AD was significantly associated in random effect model for SNP rs3846662 (HMGCR; OR = 1.16, 95% CI = 0.99, 1.35, I[2] = 59%, p = 0.06), rs11136000 (CLU; OR = 1.15, 95% CI = 1.08, 1.22, I[2] = 0%, p = 0.83), rs754203 (CYP46A1; OR = 1.10, 95% CI = 0.92, 1.33, I[2] = 87%, p < 0.01), and rs3851179 (PICALM; OR = 1.18, 95% CI = 1.05, 1.33, I[2] = 77%, p < 0.01).

CONCLUSION: The selected SNPs were found to be significantly associated with the risk of AD, with risk alleles for rs3846662, rs11136000, rs754203, and rs3851179 being G, C, T, C alleles respectively with an OR of 1.16, 1.15, 1.10, and 1.18 respectively. Therefore, these can be considered to be AD biomarkers.},
}

Humans
*Alzheimer Disease/genetics/diagnosis
*Biomarkers/blood
Polymorphism, Single Nucleotide
Genetic Predisposition to Disease
Cholesterol/metabolism

@article {pmid41500650,
year = {2025},
author = {Tirambulo, CVG and Merlini, S and Paul, M and Lizarraga, C and Brinton, RD and Vitali, F},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105280},
doi = {10.1002/alz70856_105280},
pmid = {41500650},
issn = {1552-5279},
mesh = {Humans ; Female ; *Biomarkers/blood ; Male ; *Alzheimer Disease/blood/genetics/diagnosis ; Aged ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Middle Aged ; Apolipoprotein E4/genetics ; Registries ; Risk Factors ; },
abstract = {BACKGROUND: Individuals in the early stages of Alzheimer's disease (AD) constitute a heterogeneous group, with diverse risk factor profiles such as chromosomal sex, apolipoprotein E (APOE) genotype, and comorbidities, evolving over distinct time courses. Within a prodromal phase that can extend for one to three decades, opportunities and challenges exist in identifying crucial tipping points in progression and opportunities for prevention.

METHOD: Our study aimed to identify subgroups within the 389 individuals at high-risk for AD (65.6±6.4 years old, 67.1% female, 38.8% APOE ε4 carriers) from the Wisconsin Registry for Alzheimer's Prevention data, 2001-2022. We analyzed prospectively collected data covering patient characteristics (age, sex, race, and APOE ε4 carrier status), medical history (history of diabetes, hypertension, and hyperlipidemia), plasma biomarkers (amyloid-β (Aβ) 40, Aβ42, Aβ40/42 ratio, phosphorylated tau (p-tau) 181, and p-tau 217), and blood laboratory parameters (insulin, glucose, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol). Employing classical clustering methodologies (CCMs, k-means (KMs), KMs with principal component analysis, hierarchical clustering (HC), and HC with dynamic time warping) to inform the unsupervised deep embedded clustering (DEC) algorithm, we evaluated cluster membership and assessed clinical validity. Variable contributions to the predicted cluster membership were assessed using SHapley Additive exPlanations values.

RESULT: Our DEC findings demonstrated promising results by identifying more distinct risk profile patterns for each cluster (n = 6) compared to CCMs (n = 2); achieving a more evenly distributed partitioning of participants into clusters with increased stability, measured by Jaccard and entropy scores; and validating the clinical recognizability based on laboratory values, plasma biomarkers, physician cognitive diagnoses, and Preclinical Alzheimer Cognitive Composite scores. Cluster characterization revealed participants in cluster 6 (n = 44) were most at-risk for AD, consisting of female APOE ε4 carriers with elevated p-tau levels. Conversely, cluster 4 (n = 57) was the least at-risk, youngest cluster, comprising females with fewer comorbid conditions and the lowest AD biomarker levels. Cluster 3 (n = 81) represented the control population.

CONCLUSION: Going forward, these outcomes will enable a robust pipeline for integrating electronic medical record data, empowering diverse patient characterization, and better identify those at risk to implement personalized preventative treatment within heterogeneous populations at risk for AD.},
}

Humans
Female
*Biomarkers/blood
Male
*Alzheimer Disease/blood/genetics/diagnosis
Aged
Amyloid beta-Peptides/blood
tau Proteins/blood
Middle Aged
Apolipoprotein E4/genetics
Registries
Risk Factors

@article {pmid41499862,
year = {2025},
author = {Nadais, A and Castro, C and Martins, I and Trigo, D and Nunes, C and Henriques, AG and de Lourdes Pereira, M and da Cruz E Silva, OAB},
title = {Nanoparticle-mediated Zn delivery impacts neural protein phosphatase activity.},
journal = {Biomaterials advances},
volume = {182},
number = {},
pages = {214675},
doi = {10.1016/j.bioadv.2025.214675},
pmid = {41499862},
issn = {2772-9508},
abstract = {In recent years, the use of nanoparticles (NPs) in diagnosis and treatment of different disorders has been a matter of intensive research. Due to their physical and chemical properties, zinc oxide nanoparticles (ZnO NP) have been explored in a range of biological applications, including cancer and neurological diseases. Regarding the latter, while some studies report protective effects of ZnO NP in cultured cells and animal models, others indicate that these NPs have a harmful impact on the brain, such as promoting oxidative stress and cell death. Previous results from our group have suggested beneficial effects for zinc (Zn) cations in both modulating protein aggregation and on Alzheimer's disease (AD) pathology. In this context, the effect of encapsulated Zn as a nanoparticle on protein aggregation and its influence on protein phosphorylation events associated with AD were explored. The results herein presented show that ZnO NP contributed to a decrease in protein aggregation in neuronal cells. However, these NPs were also found to decrease PP1 and PP2A activity, potentially contributing to increased phosphorylation of tau and APP, which are AD pathology hallmarks. In conclusion, while the use of NPs as a Zn delivery system may offer benefits by reducing aggregate formation, they also appear to induce undesired molecular changes, like those observed in AD. Therefore, a holistic approach should be incorporated as we move forward in this research line, as their effects on distinct cellular processes may be dual edged.},
}

@article {pmid41499797,
year = {2025},
author = {Grigoli, MM and Pachane, BC and Fuzer, AM and de Oliveira, SD and Targas, ABA and Alexandre-Silva, V and Selistre-de-Araujo, HS and Manzine, PR and Cominetti, MR},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e105542},
doi = {10.1002/alz70856_105542},
pmid = {41499797},
issn = {1552-5279},
mesh = {Humans ; Tretinoin/pharmacology ; Cell Line, Tumor ; *Cell Differentiation/drug effects/physiology ; Laminin/pharmacology ; Biomarkers/metabolism ; *Neurons/drug effects/metabolism ; Acetylcholinesterase/metabolism ; Neuroblastoma/pathology ; Tubulin/metabolism ; Neurites ; Extracellular Matrix/metabolism ; },
abstract = {BACKGROUND: The SH-SY5Y neuroblastoma cell line is a valuable in vitro model for studying neuronal differentiation and neurodegenerative diseases like Alzheimer's disease (AD). Traditional differentiation protocols mainly use retinoic acid (RA); however, they lack extracellular matrix (ECM) components that are critical for mechanotransduction and cellular adhesion, which limits their physiological relevance. Laminins, a key ECM glycoprotein, play an essential role in neurite outgrowth and synaptic formation, indicating their potential to enhance neuronal differentiation.

METHOD: SH-SY5Y cells were cultured in DMEM/F12 supplemented with fetal bovine serum (FBS) and essential additives. Differentiation was induced using RA (10 µM and 25 µM) and a laminin-rich ECM (LrECM). Plates were pre-coated with Matrigel® (a laminin-rich ECM) before seeding the cells. Differentiation efficiency was monitored over 10 days through light microscopy, immunofluorescence for neuronal markers (NeuN and β3-tubulin), and acetylcholinesterase (AChE) activity assays. Western blotting assessed β3-tubulin expression, and neurite lengths were quantified using FIJI software.

RESULT: The combined RA and LrECM treatment significantly enhanced SH-SY5Y differentiation when compared to RA alone. Neuronal morphology, marked by extensive neurite outgrowth, became evident as early as day 4 and was sustained for up to 10 days. Immunofluorescence confirmed increased NeuN expression, showing a shift from cytoplasmic to perinuclear localization over time. β3-tubulin levels remained consistently high in LrECM-treated cells, unlike those treated with RA alone, which demonstrated a decline after day 7. Enhanced cholinergic differentiation was indicated by elevated AChE activity, particularly at 25 µM RA, although higher RA concentrations were unable to sustain neuronal characteristics and raised concerns about cytotoxicity.

CONCLUSION: The incorporation of LrECM into SH-SY5Y differentiation protocols significantly enhances neuronal differentiation and maintains neuron-like characteristics, providing a more physiologically relevant in vitro model for studying AD and other neurodegenerative diseases. This approach enables cost-effective, rapid differentiation and more accurately mimics the brain microenvironment, establishing a strong platform for neurobiological research and therapeutic screening.},
}

Humans
Tretinoin/pharmacology
Cell Line, Tumor
*Cell Differentiation/drug effects/physiology
Laminin/pharmacology
Biomarkers/metabolism
*Neurons/drug effects/metabolism
Acetylcholinesterase/metabolism
Neuroblastoma/pathology
Tubulin/metabolism
Neurites
Extracellular Matrix/metabolism

@article {pmid41499417,
year = {2025},
author = {Young, AL and Wijeratne, PA and Aksman, LM and Binette, AP and Strandberg, O and Oxtoby, NP and Altmann, A and Alexander, DC and Stomrud, E and Palmqvist, S and Mattsson-Carlgren, N and Vogel, JW and Hansson, O},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104804},
doi = {10.1002/alz70856_104804},
pmid = {41499417},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/metabolism/cerebrospinal fluid ; Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/pathology ; Male ; Female ; *Biomarkers/cerebrospinal fluid/metabolism ; Aged ; Disease Progression ; *Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Sweden ; *Brain/diagnostic imaging/metabolism ; Middle Aged ; *Amyloid/metabolism ; },
abstract = {BACKGROUND: Amyloid and tau accumulation in Alzheimer's disease is known to be dynamic, with expected rates of accumulation varying depending on disease stage. Establishing the precise timeline of amyloid and tau accumulation and quantifying their dynamic progression is important for identifying an optimal intervention window and predicting treatment response.

METHOD: 960 individuals were selected from the Swedish BioFINDER-2 study with at least two tau-PET scans (Table 1; follow-ups were at 1 year (N = 66), 2 years (N = 924), 4 years (N = 335); 6 years (N = 60)). Two intersecting data subsets were selected: 773 individuals having at least two amyloid-PET scans for estimating amyloid duration, and 434 CSF-amyloid-positive individuals for comparison with timelines across the whole population. Regional tau-PET SUVR abnormality was computed in five established data-driven regions using mixture modelling. A novel explicit-duration version of the temporal event-based model (T-EBM) was used to determine the order and timeline of global amyloid-PET and regional tau-PET abnormality. The explicit duration approach accounts for censoring of an individual's first and last visit and handles arbitrary time intervals.

RESULT: The T-EBM inferred that tau accumulates in a Braak-like pattern (Figure 1a), estimating an average timeline of global amyloid and regional tau accumulation (Figure 1b) of around 20 years. Progression from stage 1 (amyloid) to stage 2 (entorhinal tau) was estimated to take 8 years on average, from stage 2 to stage 3 (temporal lobe tau) 5.5 years, and 2-3 years between each subsequent stage. The timeline was consistent in amyloid-positive individuals (most amyloid-negative individuals were stage 0 and did not influence the timeline). Figure 1c shows the number of individuals progressing between stages at follow-up. Individuals who progressed in stage (progressors) were older, had more advanced symptoms (diagnosis), more APOE4 alleles, worse MMSE scores, and were more frequently amyloid-positive compared to non-progressors (Table 2).

CONCLUSION: Amyloid accumulates slowly, after which tau spreads from the entorhinal cortex to the temporal lobe, initially at a slower pace before accelerating to a faster rate across the cortex. This data indicates that slower rates of accumulation would be expected at earlier stages. Work is ongoing validating these timelines in additional datasets.},
}

Humans
*tau Proteins/metabolism/cerebrospinal fluid
Positron-Emission Tomography
*Alzheimer Disease/diagnostic imaging/metabolism/cerebrospinal fluid/pathology
Male
Female
*Biomarkers/cerebrospinal fluid/metabolism
Aged
Disease Progression
*Amyloid beta-Peptides/metabolism/cerebrospinal fluid
Sweden
*Brain/diagnostic imaging/metabolism
Middle Aged
*Amyloid/metabolism

@article {pmid41499318,
year = {2026},
author = {Melrose, J},
title = {Roles for Electrochemical Proton Gradients in Mitochondrial Energy Production and Neurosensory Processes in Health and Disease.},
journal = {Developmental neurobiology},
volume = {86},
number = {1},
pages = {e70006},
doi = {10.1002/dneu.70006},
pmid = {41499318},
issn = {1932-846X},
support = {//Melrose Personal Research Fund/ ; },
mesh = {Humans ; Animals ; *Mitochondria/metabolism ; *Energy Metabolism/physiology ; *Protons ; *Proton-Motive Force/physiology ; *Nervous System Diseases/metabolism ; Oxidative Stress/physiology ; },
abstract = {This study reviews the roles of proton electrochemical gradients in ubiquitous mitochondrial energy production systems in cellular activation and functions in neurosensory signaling. Proton electrochemical gradients crucially shaped the evolution of life. The emergence of the proton-motive force in mitochondria was fundamental in energy production and central to the function of eukaryotic cells. Dysfunctional mitochondria, however, result in impaired formation of proton gradients and a wide spectrum of diseases. This is particularly prominent in tissues with high energetic demands, such as muscle and nervous tissues. Oxidant stress generated by dysfunctional proton conductance in the brain results in Alzheimer's and Parkinson's disease, muscular sclerosis, amyotrophic sclerosis, and Huntington's disease. In these disorders, oxidative stress, protein misfolding, and neuroinflammation lead to dysfunctional neuronal activity, neuronal damage, and death. Advancements in nanozyme-engineered synthetic enzymes offer a promising innovative approach to the treatment of these disorders. Nanozymes target proton conductance and the oxidant species they generate, scavenging oxygen free radicals and restoring redox balance, and offer neuronal protection and functional recovery of brain tissues. Neural injury and associated neurological diseases affect almost 1 billion people globally, so there is a clear need to develop effective methods that stimulate neural repair and regeneration. Glycosaminoglycans with proton capture and transport properties regulate intercellular signaling processes, synaptic functions, and cellular communication. Electroconductive hydrogels are showing impressive results in neural repair and regeneration. Glycosaminoglycans, particularly keratan sulfate, show useful electroconductive proton capture and transport properties, suggesting they may be worth evaluation in such procedures.},
}

Humans
Animals
*Mitochondria/metabolism
*Energy Metabolism/physiology
*Protons
*Proton-Motive Force/physiology
*Nervous System Diseases/metabolism
Oxidative Stress/physiology

@article {pmid41499301,
year = {2026},
author = {Mohasel-Roodi, M and Nozari, M and Shamsara, A and Basiri, M and Mirzaie, V and Baghalishahi, M},
title = {Effects of Dexmedetomidine on the Behavioral Outcomes in Streptozotocin-Induced Alzheimer's Disease Rats.},
journal = {Brain and behavior},
volume = {16},
number = {1},
pages = {e71196},
doi = {10.1002/brb3.71196},
pmid = {41499301},
issn = {2162-3279},
support = {402000357//Kerman Neuroscience Research Center, Kerman University of Medical Sciences/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced ; *Dexmedetomidine/pharmacology/administration & dosage ; Streptozocin/pharmacology ; Rats, Wistar ; Male ; Rats ; *Behavior, Animal/drug effects ; Anxiety/drug therapy ; Maze Learning/drug effects ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; *Adrenergic alpha-2 Receptor Agonists/pharmacology ; Cognitive Dysfunction/drug therapy ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive and prevalent neurodegenerative disorder characterized by progressive cognitive decline and memory impairment. Intracerebroventricular (ICV) administration of streptozotocin (STZ) in rodents recapitulates key features of sporadic AD, including brain insulin resistance and oxidative stress. Dexmedetomidine (Dex), a highly selective α2-adrenergic receptor agonist, has demonstrated neuroprotective and anti-inflammatory properties, suggesting its potential utility as a therapeutic approach for AD.

METHODS: Seventy adult male Wistar rats were randomly allocated to seven experimental groups: Control, Sham, STZ, Sham + Dex (25 µg/kg), and STZ + Dex (25, 50, 100 µg/kg). Cognitive performance and anxiety-like behaviors were evaluated using the open-field test (OFT), elevated plus maze (EPM), Y-maze test, and Morris water maze (MWM).

RESULTS: In the Y-maze, STZ-treated rats exhibited significant reductions in spontaneous alternation behavior (p = 0.002), which were significantly reversed by Dex (25 µg/kg, p = 0.002). In the MWM, the STZ administration resulted in prolonged escape latencies and increased path lengths compared with Control animals (p < 0.05). Treatment with Dex (25 µg/kg) significantly improved spatial learning and memory retention (p < 0.05). No significant differences were observed in locomotor activity and anxiety-related behaviors in the OFT or EPM.

CONCLUSIONS: These findings indicate that Dex at 25 µg/kg attenuates STZ-induced cognitive deficits, likely through neuroprotective and anti-inflammatory mechanisms. The results highlight Dex as a promising candidate for AD therapy, though further research is required to elucidate its underlying molecular pathways. The study supports the potential repurposing of Dex for neurodegenerative disorders.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced
*Dexmedetomidine/pharmacology/administration & dosage
Streptozocin/pharmacology
Rats, Wistar
Male
Rats
*Behavior, Animal/drug effects
Anxiety/drug therapy
Maze Learning/drug effects
Disease Models, Animal
Neuroprotective Agents/pharmacology
*Adrenergic alpha-2 Receptor Agonists/pharmacology
Cognitive Dysfunction/drug therapy

@article {pmid41498900,
year = {2026},
author = {Lin, ZY and Cai, LL and Lin, JX and Zheng, GY},
title = {Tiaobu Xinshen Recipe Improves Cognitive Deficits by Alleviating Synaptic Ultrastructure Degradation and Reducing Amyloid β in Transgenic Mice of Alzheimer's Disease.},
journal = {Chinese journal of integrative medicine},
volume = {},
number = {},
pages = {},
pmid = {41498900},
issn = {1993-0402},
abstract = {OBJECTIVE: To investigate the effect of Tiaobu Xinshen Recipe (TXR) on cognitive function of 5xFAD transgenic mice and explore the potential mechanisms.

METHODS: Six-month-old male wild-type (WT) mice and 5xFAD transgenic mice were randomly divided into vehicle (0.9% NaCl), TXR (granules, 4.18 g/kg) and donepezil (0.625 mg/kg) groups using a random number table, respectively, which were given intragastric administration once a day for 60 d. Spatial learning and memory performance was tested with modified Morris water maze (MMWM) test. Synaptic ultrastructure in the hippocampal CA1 region was observed by transmission electron microscopy. The levels of amyloid β (Aβ), the major amyloid precursor protein (APP)-cleaving enzymes and Aβ-degrading enzymes including β-secretase, α-secretase, neprilysin (NEP) and insulin-degrading enzyme (IDE), were detected by immunohistochemistry staining and Western blot, respectively.

RESULTS: In MMWM test, when compared with the 5xFAD-vehicle group, 5xFAD-TXR group demonstrated a significantly shorter escape latency to the platform and increased number of platform crossings and time spent in target quadrant (P<0.05 or P<0.01). The ultrastructure of synapse in the hippocampal CA1 region of mice in the 5xFAD-TXR group was significantly changed, including increased numbers of mitochondria and synaptic vesicles, intact synaptic membrane, and thickened postsynaptic density. The Aβ load was markedly decreased in the cerebral cortex and hippocampus CA1 subregion of TXR-treated 5xFAD mice (P<0.05). TXR treatment decreased APP levels and increased IDE expression in brains of 5xFAD mice (P<0.01). However, TXR treatment had no effect on α- and β-secretase, and NEP in 5xFAD mice (P>0.05).

CONCLUSION: TXR improves cognitive dysfunction in 5xFAD mice by alleviating synaptic ultrastructure degradation and reducing Aβ.},
}

@article {pmid41498751,
year = {2025},
author = {Biel, D and Steward, A and Dewenter, A and Dehsarvi, A and Zhu, Z and Roemer-Cassiano, S and Frontzkowski, L and Hirsch, F and Brendel, M and Franzmeier, N},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104771},
doi = {10.1002/alz70856_104771},
pmid = {41498751},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; *tau Proteins/blood ; Aged ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Longitudinal Studies ; *Cognitive Dysfunction/diagnostic imaging ; Amyloid beta-Peptides ; Aged, 80 and over ; Brain/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: With the approval of anti-amyloid therapies in Alzheimer's disease (AD), surrogate biomarkers are urgently needed to monitor treatment effects that translate into clinical benefits. Candidate biomarkers, including amyloid-PET, tau-PET, plasma phosphorylated tau (p-tau), and MRI-assessed atrophy, capture core pathophysiological changes in AD. While cross-sectional biomarker assessments are critical for diagnosis and staging, biomarker change rates may better reflect disease dynamics, making them more suitable for monitoring treatment efficacy. Therefore, we determined which biomarker most effectively tracks cognitive changes in AD, identifying those best suited for efficient monitoring of disease-modifying treatments.

METHOD: We leveraged ADNI (N = 108) and A4 (N = 151) participants with longitudinal AD biomarker data (global amyloid-PET, temporal meta tau-PET, plasma p-tau217, MRI-assessed cortical thickness in the AD signature region) together with cognitive assessments (ADNI: MMSE, ADAS13, CDR-SB; A4: MMSE, PACC). Linear mixed models were used to calculate change rates for biomarkers and cognition. To test whether biomarker changes track cognitive decline, linear models were applied, to test biomarker change rates as a predictor of cognitive change rates. Standardized beta values from bootstrapped linear models were extracted to compare the strengths of correlations between biomarkers and cognitive decline. For non-parametric comparisons, 95% confidence intervals (CIs) of standardized beta values were compared. Models were controlled for age, sex, education, and baseline cognition, with ADNI models additionally adjusted for clinical status.

RESULT: In both cohorts, changes in temporal tau-PET, plasma p-tau217, and MRI-assessed cortical thickness were associated with cognitive decline (ADNI: Figure 1; A4: Figure 2). Amyloid-PET changes showed no significant association with cognitive changes (ADNI: Figure 1A+F+K; A4: Figure 2A+F). Bootstrapping confirmed that tau-PET, plasma p-tau217, and cortical thickness track cognitive decline, but not amyloid-PET (ADNI: Figure 1E+J+O; A4: Figure 2E+J). Overlapping CIs for tau-PET and plasma p-tau217 indicated comparable predictive accuracy.

CONCLUSION: Our findings demonstrate that tau-PET and plasma p-tau217 are robust biomarkers for monitoring cognitive changes, with plasma p-tau217 offering a cost-effective, scalable alternative for clinical use. Changes in amyloid-PET do not reliably reflect cognitive decline, limiting its utility as a treatment monitoring tool. Although cortical thickness correlates with cognitive changes, its application is limited by pseudoatrophy and volume loss induced by anti-amyloid antibody treatments.},
}

Humans
*Biomarkers/blood
Male
Female
*Alzheimer Disease/diagnostic imaging/pathology/metabolism
*tau Proteins/blood
Aged
Magnetic Resonance Imaging
Positron-Emission Tomography
Longitudinal Studies
*Cognitive Dysfunction/diagnostic imaging
Amyloid beta-Peptides
Aged, 80 and over
Brain/pathology/diagnostic imaging

@article {pmid41498704,
year = {2025},
author = {Bathe, T and Salomasova, S and Lalia, M and Kunze, LH and Palumbo, G and Oos, R and Joseph, E and Brendel, M},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104796},
doi = {10.1002/alz70856_104796},
pmid = {41498704},
issn = {1552-5279},
mesh = {Animals ; *Biomarkers/cerebrospinal fluid/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Alzheimer Disease/drug therapy ; Positron-Emission Tomography ; tau Proteins/metabolism ; Humans ; Brain/metabolism/pathology/diagnostic imaging/drug effects ; *Tauopathies/drug therapy ; Microglia/metabolism ; },
abstract = {BACKGROUND: The prevalence of neurodegenerative diseases (ND), including Alzheimer's disease (AD) and non-AD tauopathies, is projected to rise significantly by 2050 due to an aging global population. Chronic neuroinflammation, driven by glial activation in response to protein pathologies, is a major contributor to disease progression. Targeting glial dysfunction through immunomodulatory therapies offers a promising approach to mitigate the effects of tauopathies and other ND.

METHOD: PS19 mice receive chronic treatment with GV1001 over 5 months. Serial neuroimaging techniques, including PET scans targeting tau protein, microglial activation, and astrocytic responses, are employed to assess treatment effects in vivo (Figure 1). Postmortem validation is performed using immunohistochemistry and biochemical methods, comparing treated mice to placebo and non-transgenic controls.

RESULT: The research scope is to monitor the efficacy of GV1001 in a transgenic tau mouse model (PS19) with an early-intervention biomarker study using molecular biology and neuroimaging techniques including TSPO (microglia) PET, deprenyl (astroglia) PET, tau PET (perfusion and retention) and CSF markers of inflammation (e.g. sTREM2) and neurodegeneration (NfL). Preliminary findings, expected to be presented at the conference, will provide insights into the drug's ability to modulate glial activity, restore homeostasis, and reduce tau pathology.

CONCLUSION: This study highlights the potential of monitoring immunomodulatory strategies to address the complex interplay between chronic neuroinflammation and protein aggregation in ND. If successful, these findings could inform the development of novel therapeutic approaches for AD and related disorders, bridging the gap between preclinical research and clinical application.},
}

Animals
*Biomarkers/cerebrospinal fluid/metabolism
Mice
Mice, Transgenic
Disease Models, Animal
*Alzheimer Disease/drug therapy
Positron-Emission Tomography
tau Proteins/metabolism
Humans
Brain/metabolism/pathology/diagnostic imaging/drug effects
*Tauopathies/drug therapy
Microglia/metabolism

@article {pmid41498508,
year = {2025},
author = {Doecke, JD and Chenna, A and Lo, M and Badal, Y and Yee, B and Martone, RL and Petropoulos, C and Fowler, CJ and Laws, SM and Rainey-Smith, SR and Martins, RN and Rowe, CC and Masters, CL and Winslow, JW},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104702},
doi = {10.1002/alz70856_104702},
pmid = {41498508},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; *Amyloid beta-Peptides/blood/metabolism ; Male ; Female ; *Cognitive Dysfunction/blood/diagnostic imaging/diagnosis ; Aged ; *Alzheimer Disease/blood/diagnostic imaging/diagnosis ; *tau Proteins/blood ; Peptide Fragments/blood ; Cohort Studies ; Positron-Emission Tomography ; Aged, 80 and over ; Australia ; Middle Aged ; },
abstract = {BACKGROUND: With the increasing number of countries approving disease-modifying therapies (DMTs) for patients with either Mild Cognitive Impairment (MCI) or mild Alzheimer's disease (AD), it is vitally important to streamline treatment assessment processes. Blood-based biomarkers (BBMs) have been suggested as rivals to cerebrospinal fluid (CSF) biomarkers in their accuracy to detect neocortical Amyloid-Beta (Aβ). However, there is little consensus on potential thresholds and resulting confirmatory test performance for international use in target populations.

METHOD: Two separate sub-cohorts-the AD continuum cohort (ADCC) [cognitively impaired + unimpaired; N = 197] and the intention to treat cohort (ITTC) [cognitively impaired; N = 200]-from the Australian Imaging Biomarkers and Lifestyle (AIBL) study of aging, were designed to test the accuracy and potential cut-offs of leading BBM Lumipulse assays from Fujirebio (pTau217 and Aβ42/40) to detect PET-Aβ (centiloid ≥25; amyloid prevalence ∼63%).

RESULT: Using the pTau217/Aβ42 ratio significantly improved the area under the curve (AUC) over pTau217 alone to detect PET-Aβ positivity in both the ADCC and ITTC (Figure 1A, ADCC p = 0.01; Figure 1B: ITTC p = 0.009). The Youden's Index cut-off for pTau217 was higher in the ITTC compared to the ADCC (0.25 pg/mL vs. 0.179 pg/mL). The highest accuracy observed for either single BBMs, the ratio of BBMs, or the linear combination of BBMs that included age, gender, and APOE ε4 was 93-95% in the ADCC (linear combination of pTau217, Aβ42/40, age, gender, and APOE ε4; pTau217/Aβ42 ratio) and 95-97% in the ITTC (linear combination; pTau217/Aβ42 ratio). The lowest number of participants in the intermediate zone using dual cut-offs at 95% sensitivity and specificity was 9% and 14% for the pTau217/Aβ42 ratio in the ADCC and ITTC (92-93% accuracy), and 0% for the linear combination (pTau217, Aβ42/40, age, gender, and APOE ε4) in the ITTC (95% accuracy).

CONCLUSION: The general performance of the Lumipulse assays was similar across both the ADCC and ITTC, indicating strong repeatability independent of clinical stage. Focusing on only participants eligible for DMTs increased sensitivity and improved accuracy for the Aβ-containing pTau217/Aβ42 ratio and linear combination of markers, and resulted in small numbers of unclassified participants by the test.},
}

Humans
*Biomarkers/blood
*Amyloid beta-Peptides/blood/metabolism
Male
Female
*Cognitive Dysfunction/blood/diagnostic imaging/diagnosis
Aged
*Alzheimer Disease/blood/diagnostic imaging/diagnosis
*tau Proteins/blood
Peptide Fragments/blood
Cohort Studies
Positron-Emission Tomography
Aged, 80 and over
Australia
Middle Aged

@article {pmid41498480,
year = {2026},
author = {Goodall, LS and Lennon, MJ and Sachdev, PS and Gorelick, PB and Kovacic, JC and Samaras, K},
title = {Current and Emerging Therapeutic Approaches for Vascular Cognitive Impairment and Dementia.},
journal = {Journal of the American College of Cardiology},
volume = {87},
number = {1},
pages = {77-100},
doi = {10.1016/j.jacc.2025.09.1502},
pmid = {41498480},
issn = {1558-3597},
mesh = {Humans ; *Dementia, Vascular/therapy/prevention & control ; *Cognitive Dysfunction/therapy ; },
abstract = {Cardiovascular risk factors contribute to the majority of dementia cases, with about 20% directly attributable to vascular cognitive impairment and dementia (VCID). VCID treatment developments have been slow compared with Alzheimer's disease (AD), which now has several FDA-approved symptom- and disease-modifying agents. In the second part of this JACC Seminar Series, advances and new perspectives on the management and prevention of VCID are reviewed. There is reasonable evidence that cognitive enhancers (donepezil, galantamine, and memantine) modestly improve cognition in vascular dementia (VaD), the most severe form of VCID, especially if there is associated AD pathology. Antidepressants may benefit those with depression and stroke, but they have poor efficacy in those with depression and VaD alone. Behavioral, social, and environmental interventions are first-line therapies for managing VCID-associated agitation and psychosis. Second-line antipsychotics have not been trialed in those with VaD alone, but are beneficial where AD and VaD co-exist, with risperidone and quetiapine effective in reducing psychosis and agitation. Primary prevention of VCID includes identifying and managing cardiometabolic risk factors along with manifestations of covert cerebrovascular disease. Both primary and secondary VCID prevention involve management of cardiovascular risks, specifically hypertension, diabetes mellitus, smoking, atrial fibrillation, obesity, and sedentariness. Management of vascular risk factors may moderately reduce the risk of incident cognitive impairment. Novel interventions currently being evaluated in clinical trials are discussed. The discovery and utilization of VCID and AD biomarkers will enhance the specificity and effectiveness of interventions such that a precision-medicine approach to disease-specific medical therapy may be taken.},
}

Humans
*Dementia, Vascular/therapy/prevention & control
*Cognitive Dysfunction/therapy

@article {pmid41498479,
year = {2026},
author = {Sachdev, PS and Bentvelzen, AC and Gustafson, D and Hansra, GK and Hosoki, S and Jiang, J and Lennon, MJ and Moro, MA and Saks, DG and Samaras, K and Kovacic, JC and Kalaria, R},
title = {Vascular Cognitive Impairment and Dementia: Clinical Features, Neuropathology, and Biomarkers.},
journal = {Journal of the American College of Cardiology},
volume = {87},
number = {1},
pages = {52-76},
doi = {10.1016/j.jacc.2025.11.008},
pmid = {41498479},
issn = {1558-3597},
mesh = {Humans ; Biomarkers/metabolism ; *Dementia, Vascular/diagnosis/pathology ; *Cognitive Dysfunction/diagnosis/etiology ; Risk Factors ; *Brain/pathology ; },
abstract = {Vascular cognitive impairment and dementia (VCID), ie, cognitive impairment secondary to cerebrovascular disease (CeVD), is the second most common form of dementia after Alzheimer's disease (AD), accounting for 15% to 20% of all cases. CeVD, in fact, contributes to dementia alongside other neuropathologies in up to 75% of dementia cases. CeVD and AD not only frequently co-occur in the brain, but they may also interact, and some VCID risk factors (midlife hypertension and diabetes) also increase AD risk. Because CeVD and cardiovascular disease share risk factors and pathophysiology, the cardiovascular clinician is likely to encounter both in the clinic. Moreover, common cardiac disorders, such as atrial fibrillation, heart failure, acute coronary syndrome, and valvular disease, increase VCID risk. There have been recent developments in the diagnostic criteria for VCID, with advances in risk biomarkers, treatment, and prevention of cognitive impairment and dementia. The diagnosis of VCID is a 2-step process, with the initial identification of a cognitive syndrome followed by the establishment of a predominantly vascular etiology, guided by clinical history and examination and substantiated by neuroimaging, preferably magnetic resonance imaging. Clinical presentations include an acute onset, a stepwise decline, a fluctuating course if caused by multiple strokes, or a gradual slow progression if attributable to cerebral small vessel disease. Cognitive deficits can be found in several domains, such as information-processing speed, attention, executive function, and emotional lability, sometimes referred to as the subcortical syndrome, often seen in the early stages of VCID without cortical infarcts. The diagnosis is supported by the identification of large and small infarcts, lacunes, white matter hyperintensities, dilated perivascular spaces and cerebral microbleeds using magnetic resonance imaging. This part 1 of a 2-part JACC review series describes the clinical features, pathophysiology, and biomarkers of VCID for cardiovascular clinicians who have a critical role in its early identification, management, and prevention in their patients.},
}

Humans
Biomarkers/metabolism
*Dementia, Vascular/diagnosis/pathology
*Cognitive Dysfunction/diagnosis/etiology
Risk Factors
*Brain/pathology

@article {pmid41498388,
year = {2025},
author = {Chiotis, K and Blazhenets, G and Eloyan, A and Maiti, P and Zhang, J and Touroutoglou, A and Kirby, K and Hammers, DB and Carrillo, MC and Dickerson, BC and Apostolova, LG and Rabinovici, GD and , },
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104661},
doi = {10.1002/alz70856_104661},
pmid = {41498388},
issn = {1552-5279},
mesh = {Humans ; Male ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; Female ; *tau Proteins/metabolism ; Biomarkers/metabolism ; *Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Longitudinal Studies ; Aged ; Cognitive Dysfunction/drug therapy/diagnostic imaging ; Middle Aged ; Brain/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: In clinical trials, monoclonal antibodies targeting Aβ pathology have shown strong target engagement, resulting in rapid Aβ clearance and a deceleration in rate of clinical decline. Now that these treatments are approved and implemented in clinical practice, we could assess their effects in observational studies involving these patients.

METHOD: We analyzed data from 20 participants with early-onset Alzheimer's disease (EOAD) in the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort, treated with Aducanumab (n = 4), Lecanemab (n = 15), or both (one transitioning from Aducanumab to Lecanemab). All participants had MCI or mild dementia at baseline, longitudinal Aβ and tau PET, as well as cognitive assessments, with at least one observation before and after treatment initiation. We applied piecewise regression with a knot at the treatment start, to evaluate changes in Aβ and tau PET burden and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. We compared the trajectories of treated participants with an untreated group (i.e., treated-untreated comparison) from LEADS, matched for age, sex, APOE ε4 genotype, pretreatment Aβ and tau PET load, CDR-SB, and follow-up duration, using a 1:3 matching design.

RESULT: The median treatment duration was 8 months (IQR=5-10). In the piecewise regression model, the treated group showed significant decreases in Aβ burden post-treatment (Δ=-52 Centiloids/yr, p <0.001) with widespread neocortical involvement (Figure 1). However, no significant inflection in tau burden (Δ=0 SUVR/yr, p = 0.58) or CDR-SB (Δ=0.3 units/yr, p = 0.57) trajectories was observed. In the treated-untreated comparison, the treated group showed a trend toward slower increases in CDR-SB scores post-treatment (ΔT=-1.8, p = 0.07) compared to the untreated group (Figure 2). Aβ levels significantly decreased in the treated group compared to the untreated group (ΔΤ=-8.5, p <0.001). No significant differences in tau trajectories were observed between groups (ΔT=0.4, p = 0.68), with both showing increases in cortical regions of interest.

CONCLUSION: We observed excellent target engagement, with piecewise regression models showing rates of Aβ clearance comparable to those seen in Phase 3 trials. The study was underpowered to detect cognitive benefits, which are limited over a short follow-up interval. These findings underscore the utility of observational studies with biomarker data in evaluating treatment efficacy, offering insights that complement traditional randomized trials.},
}

Humans
Male
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
Female
*tau Proteins/metabolism
Biomarkers/metabolism
*Amyloid beta-Peptides/metabolism
Positron-Emission Tomography
*Antibodies, Monoclonal, Humanized/therapeutic use
Longitudinal Studies
Aged
Cognitive Dysfunction/drug therapy/diagnostic imaging
Middle Aged
Brain/diagnostic imaging/metabolism

@article {pmid41496378,
year = {2025},
author = {Zhao, Y and Lu, H and Jiang, X},
title = {Advance in neuroprotective effects of proanthocyanidins (PCs): Structure, absorption, bioactivities, mechanism, and perspectives.},
journal = {Pharmacological research},
volume = {223},
number = {},
pages = {108082},
doi = {10.1016/j.phrs.2025.108082},
pmid = {41496378},
issn = {1096-1186},
abstract = {With the global population growing and aging, along with increasing environmental, metabolic, and lifestyle-related risk factors, the worldwide incidence of stroke, Alzheimer's disease (AD) and other dementias, meningitis, and other neurological disorders-along with associated mortality-has risen significantly. Proanthocyanidins (PCs), which are oligomers and polymers of flavan-3-ols, are widely distributed across the plant kingdom, including in grape seeds, cinnamon, apples, cranberries, lotus seeds, and pine bark. They represent the second most abundant class of polyphenols in nature, after lignin. A substantial body of preclinical evidence indicates that PCs exert significant neuroprotective effects through multiple mechanisms. This review provides a systematic overview of the sources, structural characteristics, and bioavailability of PCs, with a focus on their pharmacological mechanisms in nervous system disease. Specifically, it examines their roles in regulating oxidative stress, neuroinflammation, protein homeostasis, apoptosis, autophagy, and key signaling pathways, including Nrf2/HO-1, CREB/BDNF, PI3K/Akt, MAPK, and NF-κB. Furthermore, this review systematically summarized the distinct structural forms of PCs, including monomers, dimers, trimers, and polymers, and explores their structure-activity relationships (SARs) in modulating the gut-brain axis. Additionally, recent advances in PCS-based nano-delivery systems and clinical studies related to neurological disorders are summarized. Growing evidence indicates that microbial metabolism in the gut serves as a key mechanism underlying their neuroprotective effects. Finally, the potential applications of PCs as promising dietary supplements or therapeutic agents for the prevention and treatment of nervous system diseases are discussed, along with existing challenges and future perspectives.},
}

@article {pmid41496364,
year = {2026},
author = {Facchinetti, R and Valenza, M and Ciarla, C and Steardo, L and Serviddio, G and Palombelli, G and Verkhratsky, A and Steardo, L and Canese, R and Cassano, T and Scuderi, C},
title = {Ultramicronized palmitoylethanolamide restores astrocyte-neuron metabolic coupling and Klotho/FGF21 signaling in a triple-transgenic mouse model of Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {118965},
doi = {10.1016/j.biopha.2025.118965},
pmid = {41496364},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD), a multifactorial neurodegenerative disorder, is characterized by metabolic deficiency, neuroinflammation, and synaptic impairment. Astrocyte-neuron metabolic coupling regulates cerebral energy homeostasis through key metabolites such as lactate, glutamate, and taurine. We investigated the therapeutic potential of ultramicronized-palmitoylethanolamide (um-PEA) in restoring the homeostasis of these metabolites in the triple transgenic (3 ×Tg-AD) mouse model of AD. Using in vivo magnetic resonance imaging and spectroscopy (MRI/MRS) combined with Western blot, we evaluated the effects of chronic um-PEA treatment on lactate-glutamate dynamics and taurine metabolism in the frontal cortex and hippocampus of 6- and 12 month-old mice. Our findings demonstrate that 3 ×Tg-AD mice exhibit lactate accumulation, glutamine/glutamate imbalance, and taurine depletion, alongside reduced expression of metabolic processes regulators such as FGF21, Klotho, and insulin receptor. Treatment with um-PEA successfully restored these metabolic changes by: (i) rebalancing lactate-glutamate metabolism, (ii) increasing taurine synthesis and transport, (iii) upregulating FGF21, Klotho, and insulin receptor expression, and (iv) modulating the metalloproteases ADAM10 and ADAM17, which regulate Klotho processing. These results identify um-PEA as a promising metabolic modulator capable of mitigating AD-related neurodegenerative processes. By targeting astrocyte-neuron metabolism and enhancing both FGF21 and Klotho pathways, um-PEA holds significant potential as an adjunctive therapeutic strategy for AD.},
}

@article {pmid41496361,
year = {2026},
author = {Huzián, O and Nagy, LI and Hackler, L and Knapp, L and Kocsis, ÁK and Szöts, I and Tamás, G and Puskás, LG and Molnár, G},
title = {Novel drug candidate binds to delta subunit containing GABAA receptors and improves spatial memory.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {118970},
doi = {10.1016/j.biopha.2026.118970},
pmid = {41496361},
issn = {1950-6007},
abstract = {The hydroxyquinoline derivative Q134R is a promising drug candidate for the treatment of Alzheimer's disease with cytoprotective and cognition-enhancing properties. Radioligand binding assays showed that Q134R reduced [[35]S]TBPS binding, consistent with modulation of the picrotoxin site or conformational states that regulate TBPS accessibility. Electrophysiological recordings in mouse brain slices revealed that Q134R significantly increased tonic inhibitory currents in cortical neurogliaform and dentate gyrus granule cells, both known to express delta subunit-containing GABAA receptors. This effect was abolished in mice deficient in the GABAA delta subunit confirming the delta subunit dependency of Q134R's action. Furthermore, in a scopolamine-induced amnesia model, Q134R treatment significantly improved spatial memory performance in wild-type mice, but not in mice lacking in the delta subunit. These results suggest that Q134R enhances tonic inhibition through delta subunit-containing GABAA receptors, which may contribute to the modulation of memory processes and serve as a protective mechanism in early-stage neurodegenerations. These receptor-mediated effects likely contribute to its broader therapeutic efficacy and may complement its previously reported interactions with signaling pathways such as NFAT and HIF-1.},
}

@article {pmid40511807,
year = {2025},
author = {Dodiya, R and Sharma, P and Israni, D and Kamal, MA and Greig, NH},
title = {Zebrafish-Based Parkinson's Disease Models: Unveiling Genetic Mechanisms and Therapeutic Pathways.},
journal = {CNS & neurological disorders drug targets},
volume = {24},
number = {12},
pages = {900-920},
pmid = {40511807},
issn = {1996-3181},
support = {AG000311//NHG: Intramural Research Program, National Institute on Aging, NIH, USA/ ; },
mesh = {Animals ; *Zebrafish/genetics ; *Parkinson Disease/genetics/therapy ; *Disease Models, Animal ; Humans ; },
abstract = {The zebrafish (Danio rerio) is widely utilised as a live vertebrate model in research on neurological development and nervous system diseases. This species exhibits various distinctive attributes that render it well-suited for investigating neurological disorders such as Parkinson's disease (PD). Zebrafish and humans have a genetic similarity of around 70%, and approximately 84% of the genes associated with human diseases have zebrafish equivalents. The genetic similarities and presence of neurotransmitters like dopamine allow scientists to study PD genes and proteins. Zebrafish are often challenged with neurotoxins to induce Parkinsonian symptoms, allowing researchers to evaluate attendant biochemical pathways. Zebrafish can also repair damaged organs, increasing their potential value in PD research. Because of their regenerative capacity and genetic resemblance to humans, these species can be used to study dopamine neurodegeneration and prospective PD treatments. In addition to PD, zebrafish are helpful models for studying Huntington's disease, Alzheimer's disease, epilepsy, depression, schizophrenia, and anxiety disorders. This article emphasizes significant findings of relevance to PD using the zebrafish model, describing its challenges and benefits. The investigation of key genes, protein pathways, and neurotoxins provides the opportunity to facilitate understanding of the role of dopamine neurotransmitters in PD and expedite the development of potentially promising therapeutic strategies.},
}

Animals
*Zebrafish/genetics
*Parkinson Disease/genetics/therapy
*Disease Models, Animal
Humans

@article {pmid41495612,
year = {2025},
author = {Yang, G and Zhu, D and Zhang, K},
title = {Nose-brain axis: A bridge from the nasal cavity to the central nervous system.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01770},
pmid = {41495612},
issn = {1673-5374},
abstract = {The nose-brain axis is a direct pathway linking the nasal cavity to the central nervous system. Odors, as well as exogenous substances such as pathogens, inflammatory mediators, and drugs, can enter the cranial cavity through pathways including the olfactory nerve, trigeminal nerve, and humoral routes, thereby enabling signal transmission and material exchange from the peripheral nasal cavity to the central nervous system. In recent years, advances in multimodal visualization technologies have made it possible to dynamically monitor the nose-brain axis from the molecular level to the tissue level, providing important means for revealing its functional characteristics and pathological changes. Owing to the existence of the nose-brain axis, nasal inflammation can, through neuro-immune interactions, activate central microglia and astrocytes and induce neuroinflammation, thus promoting the onset and progression of central nervous system diseases. In addition, the nose-brain axis offers a unique route for the treatment of central nervous system disorders. Intranasal drug delivery can bypass the blood-brain barrier, act directly on the central nervous system, increase intracranial drug bioavailability, and produce rapid effects, providing new ideas for treating cross-system diseases. This review systematically summarizes the anatomical pathways of the nose-brain axis, visualization monitoring technologies, and mechanisms by which nasal inflammation affects the central nervous system. It also reviews advances in intranasal drug delivery for emotional disorders, migraine, Parkinson's disease, and Alzheimer's disease, aiming to provide new strategies for studying the mechanisms by which nasal inflammation influences the central nervous system and for cross-system targeted therapy.},
}

@article {pmid41495456,
year = {2026},
author = {Chen, Z and Bi, S and Shan, Y and Wang, F and Wang, Y and Qi, Z and Wang, T and Li, X and Li, S and Xiao, H and Wang, S and Cui, B and Qi, Z and Han, Y and Yan, S and Lu, J and , },
title = {MRI-to-PET synthesis via deep learning for amyloid-β quantification in Alzheimer's disease.},
journal = {European radiology},
volume = {},
number = {},
pages = {},
pmid = {41495456},
issn = {1432-1084},
support = {82102010//National Natural Science Foundation of China/ ; 82394434//National Natural Science Foundation of China/ ; },
abstract = {OBJECTIVES: Amyloid-β (Aβ) PET is crucial for diagnosing and monitoring Alzheimer's disease (AD), but its high cost and radiation exposure limit its use. Deep learning techniques make it possible to generate PET from structured MRI data. In this study, we built a deep learning model to generate 3D synthetic Aβ PET images from structural MRI.

MATERIALS AND METHODS: The generative adversarial network with share parameters (ShareGAN) model was trained and tested with 1009 Aβ PET and paired MRI images from the Alzheimer's Disease Neuroimaging Initiative database and three tertiary hospitals in China. The 3D synthetic model operates on the whole volume rather than 2D image slices, realistically reproducing minor discrepancies between neighboring image planes. ShareGAN-based PET images were evaluated using quantitative metrics and visual assessment. Pearson correlation coefficient and Bland-Altman analyses were used to assess the correlation and concordance between synthetic and real PETs.

RESULTS: 3D Synthetic PET images showed high similarity and correlation with real Aβ PET in external testing sets 1 and 2 in terms of structural similarity index measure (0.898, 0.899), peak signal-to-noise ratio (34.690, 34.725), mean absolute error (0.031, 0.031), and standardized uptake value ratio (R = 0.758, 0.828). The diagnostic accuracy of PET positive or negative status in external testing sets 1 and 2 was 88.5% and 89.4%, respectively.

CONCLUSION: MRI-based 3D synthetic Aβ PET images can serve as a safe and cost-effective tool for Aβ status visualization, providing PET-eligible patients with Aβ PET-like imaging analysis to guide subsequent real Aβ PET scans.

KEY POINTS: Question Amyloid-β (Aβ) PET limitations (high cost, radiation, limited access) hinder early Alzheimer's disease (AD) detection. Clinical practice urgently requires a suitable supplementary method for Aβ pathology assessment. Findings AI-synthesized 3D Synthetic Aβ PET from structural MRI demonstrated strong consistency with real PET and effectively triaged high-risk patients for confirmatory scans. Clinical relevance This non-invasive, cost-effective method holds the promise of enabling wider Aβ pathology screening, reduces unnecessary PET scans, and supports early intervention in resource-limited settings, while preserving diagnostic rigor for treatment decisions.},
}

@article {pmid41494605,
year = {2026},
author = {Viqueira, L and Navarro, E and Negredo, P and Bernal, JA and Rodríguez-Franco, MI and ElenaTortosa, and López, MG},
title = {Long-term NRF2-driven microglial repopulation mitigates microgliosis, neuronal loss and cognitive deficits in tauopathy.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106253},
doi = {10.1016/j.bbi.2026.106253},
pmid = {41494605},
issn = {1090-2139},
abstract = {Tauopathies, including Alzheimer's disease, feature chronic microglial reactivity that drives neuroinflammation and disease progression. Pharmacological microglial depletion and subsequent repopulation using colony stimulating factor 1 receptor inhibitors have emerged as a potential therapeutic strategy to reprogram dysfunctional microglia. Despite promising short-term results, the long-term efficacy and pharmacological modulation of repopulated microglia remain poorly understood. Here, we investigated the long-term effects of microglial repopulation alone and in combination with the activation of the cytoprotective nuclear factor erythroid 2 p45-related factor 2 (NRF2) in an in vivo AAV-hTau[P301L] induced model. Integrating different behavioural, immunohistological and transcriptomic analysis, we evaluated cognitive function, tau pathology, neuronal survival and glial reactivity. We found that, whereas microglial repopulation alone did not significantly affect disease progression, NRF2-driven microglial replenishment sustained cognitive function, prevented hippocampal neuronal loss and restored microglial phenotype. Transcriptomic analyses further revealed that the combined treatment modulated tau- associated mitochondrial gene expression changes. These results highlight the importance of shaping the fate of self-renewed microglia and propose NRF2-mediated microglial repopulation as a potential pharmacological strategy for the treatment of tauopathies.},
}

@article {pmid41493713,
year = {2026},
author = {Hoveizi, E and Doraghi, K and Rostami, E},
title = {Fabrication and Characterization of Resveratrol-Loaded Solid Lipid Nanoparticles: Evaluation of Neuroprotective, Neurobehavioral, and Molecular Outcomes.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {346},
pmid = {41493713},
issn = {1559-1182},
support = {SCU.SB1403.12464//Shahid Chamran University of Ahvaz/ ; },
mesh = {*Resveratrol/pharmacology/administration & dosage/chemistry ; Animals ; *Nanoparticles/chemistry/ultrastructure ; *Neuroprotective Agents/pharmacology/administration & dosage/chemistry ; Male ; Rats ; Oxidative Stress/drug effects ; *Lipids/chemistry ; Antioxidants/pharmacology ; Neural Stem Cells/drug effects/metabolism ; *Behavior, Animal/drug effects ; Rats, Sprague-Dawley ; Interleukin-1beta/metabolism ; Memory/drug effects ; },
abstract = {Neurodegenerative processes involve oxidative stress, inflammation, and disrupted signaling, which contribute to cognitive decline. Resveratrol offers neuroprotection but suffers from poor solubility and bioavailability. Solid lipid nanoparticles (SLNs) can improve solubility, stability, and neural targeting, thereby enhancing efficacy. This study investigates whether SLN/resveratrol treatment modulates neuroprotective targets (HSP70, IL-1β) and antioxidant enzymes (CAT, GPX, SOD) in vitro and whether it improves inactive avoidance memory in an animal model. SLNs were produced by melting tripalmitin and palmitic acid, adding resveratrol, Tween, and butanol, then combining with water and stirring for 1 day. The resulting formulations were characterized using FTIR, electron microscopy, and DLS. Neural stem cells (NSCs) were treated with SLNs, resveratrol, and SLN/resveratrol, and the expression of oxidative stress enzymes, HSP70, and IL-1β was analyzed. In vivo, a passive avoidance memory model was induced in rats via electrical destruction of the nucleus basalis of Meynert. Molecular analysis showed that resveratrol increased HSP70 expression by 3.1-fold and significantly decreased IL-1β levels. SLN treatment had no notable effect on these genes, but the SLN/resveratrol increased HSP70 expression by fourfold and significantly reduced IL-1β. Resveratrol significantly upregulated the antioxidant enzymes CAT and GPX, whereas SLNs alone had no effect. The SLN/resveratrol also markedly enhanced CAT and GPX levels. Behavioral tests demonstrated that the SLN/resveratrol treatment improved passive avoidance memory in the Alzheimer's model. Collectively, these results indicate that SLN/resveratrol robustly enhances neuroprotection by modulating signaling pathways, reducing oxidative stress, and improving memory, with the SLN delivery system potentially increasing bioavailability and neural exposure.},
}

*Resveratrol/pharmacology/administration & dosage/chemistry
Animals
*Nanoparticles/chemistry/ultrastructure
*Neuroprotective Agents/pharmacology/administration & dosage/chemistry
Male
Rats
Oxidative Stress/drug effects
*Lipids/chemistry
Antioxidants/pharmacology
Neural Stem Cells/drug effects/metabolism
*Behavior, Animal/drug effects
Rats, Sprague-Dawley
Interleukin-1beta/metabolism
Memory/drug effects

@article {pmid41493675,
year = {2026},
author = {Usman, AS and Manoharan, SD and Che Mohd Nassir, CMN and Abdul Hamid, H and Hein, ZM and Norazit, A and Murthy, J and Zainol, M and Kamaruzzaman, MA and Chiroma, SM and Mustapha, M and Mohd Moklas, MA and Mehat, MZ},
title = {Neuroprotective Effects of Ficus deltoidea in Alzheimer's Disease-Like Rat Model: Insights from Behavior, Histology, and Amyloid Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {345},
pmid = {41493675},
issn = {1559-1182},
support = {(FRGS/1/2021/SKK0/UPM/02/15)//the Ministry of Higher Education under the Fundamental Research Grant Scheme/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism ; *Ficus/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Rats, Wistar ; Disease Models, Animal ; *Plant Extracts/pharmacology/therapeutic use ; Plaque, Amyloid/pathology/drug therapy ; Amyloid beta-Peptides/metabolism ; Hippocampus/pathology/drug effects/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Maze Learning/drug effects ; Rats ; *Behavior, Animal/drug effects ; Spatial Memory/drug effects ; Aspartic Acid Endopeptidases/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and accumulation of amyloid-β (Aβ) plaques. While current treatments offer limited efficacy, medicinal plants such as Ficus deltoidea (FD), a traditional remedy, have shown promise due to their neuroprotective and anti-inflammatory properties. An AD-like phenotype was induced in male Wistar rats using D-galactose and aluminum chloride over 70 days. FD extract was administered orally at 50, 100, and 200 mg/kg. Spatial memory was evaluated using the T-maze test. Histological analyses of the hippocampi's Cornu Ammonis 1 and 3 (CA1 and CA3) regions were conducted via hematoxylin and eosin (H&E) staining, and Aβ plaques deposition was assessed with Congo red. Enzyme-linked immunosorbent assay (ELISA) was used to quantify hippocampal levels of Aβ (1-42) and β-secretase-1 (BACE-1). FD treatment significantly enhanced spatial memory, preserved pyramidal neuron integrity in CA1 and CA3, and reduced amyloid plaque formation. Biochemically, FD markedly decreased hippocampal Aβ (1-42) and BACE-1 concentrations in a dose-dependent manner. Thus, FD exhibits multi-target neuroprotective effects in an AD-like model, potentially via modulation of amyloidogenic pathways. Further studies are warranted to explore its mechanisms and therapeutic potential in other brain regions implicated in AD.},
}

Animals
*Alzheimer Disease/pathology/drug therapy/metabolism
*Ficus/chemistry
*Neuroprotective Agents/pharmacology/therapeutic use
Male
Rats, Wistar
Disease Models, Animal
*Plant Extracts/pharmacology/therapeutic use
Plaque, Amyloid/pathology/drug therapy
Amyloid beta-Peptides/metabolism
Hippocampus/pathology/drug effects/metabolism
Amyloid Precursor Protein Secretases/metabolism
Maze Learning/drug effects
Rats
*Behavior, Animal/drug effects
Spatial Memory/drug effects
Aspartic Acid Endopeptidases/metabolism

@article {pmid41493656,
year = {2026},
author = {Cicero, CE and Angelini, L and Abbadessa, G and Bruno, M and Fiume, G and Nucera, B and Ornello, R and Arabia, G and Giuliano, L and Guarnieri, B and Lugaresi, A and Perani, D and Sacco, S and Tassorelli, C and Nicoletti, A and Pellecchia, MT and , },
title = {Sex and gender-related differences in neurological diseases: current challenges and recommendations for clinical practice.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {1},
pages = {108},
pmid = {41493656},
issn = {1590-3478},
mesh = {Humans ; *Nervous System Diseases/therapy/epidemiology ; Female ; *Sex Characteristics ; Male ; Pregnancy ; },
abstract = {Neurological diseases include a large variety of conditions ranging from inflammatory, vascular and neurodegenerative disorders to epilepsy and headache. The impact of sex and gender on various aspects of these conditions (epidemiology, risk factors, pathophysiology, clinical features, treatment, and management of pregnancy and breastfeeding) is still not entirely taken into consideration, despite a rapidly increasing body of evidence. This position paper covers six neurological conditions (Alzheimer's Disease, Cerebrovascular disease, Parkinson's disease, Epilepsy, Headache disorders, Multiple Sclerosis) providing an overview of available evidence on sex and gender differences, identifying knowledge gaps and providing recommendations for clinical practice and future studies. We recommend taking into consideration modifiable sex and gender specific risk factors, the role of hormones across women's lifespan and a personalized treatment approach based on gender. We also recommend that future efforts should be devoted to increase the representation of women in clinical studies, to promote sex and gender-based guideline production and to better characterize the safety profile in pregnancy of newer drugs.},
}

Humans
*Nervous System Diseases/therapy/epidemiology
Female
*Sex Characteristics
Male
Pregnancy

@article {pmid41491579,
year = {2026},
author = {Kamali, M and Ansari, M and Nooraee, P and Tajadini, H and Kamali, H and Dehesh, T and Ashrafzadeh, A and Sharififar, F},
title = {Preliminary clinical evaluation of capsules containing standard hydroalcoholic extract of Myrtus communis L. in patients with mild to moderate Alzheimer' disease: a randomized, double-blind parallel-group clinical trial.},
journal = {BMC complementary medicine and therapies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12906-025-04994-9},
pmid = {41491579},
issn = {2662-7671},
abstract = {BACKGROUND: This study evaluated the effectiveness of Myrtus communis L. extract, known for its antioxidant and anticholinesterase properties, to enhance cognitive function and mitigate disease progression in individuals with mild to moderate Alzheimer's disease (AD).

METHODS: Fifty elderly patients with mild to moderate AD residing in a Kerman nursing home were enrolled in a randomized, placebo-controlled trial conducted between November 2019 to February 2020. Participants were randomly assigned to either an intervention group (n = 25), receiving M. communis L. capsules (500 mg each capsule), or a control group (n = 25), receiving placebo capsules. Cognitive function was assessed at baseline and after four weeks using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scales. Statistical analyses, performed using SPSS version 22, considered a significance level of p < 0.05.

RESULTS: All fifty patients completed the four-week trial. Baseline characteristics-including sex, mean age, and education level-were well-matched between the intervention and control groups. After four weeks of treatment, the intervention group demonstrated a statistically significant improvement in cognitive function, as evidenced by significantly higher MMSE scores compared to the placebo group (23.4 ± 0.25 vs. 19.6 ± 0.25; p < 0.0001). Concurrently, the intervention group exhibited a significant reduction in dementia severity, indicated by lower CDR scores compared to the control group (0.8 ± 0.04 vs. 1.5 ± 0.04; p < 0.0001).

CONCLUSIONS: These findings suggest that M. communis L. holds promise as a potential complementary therapy for AD, capable of improving cognitive function and potentially slowing disease progression. However, further research is necessary to corroborate these results, elucidate the underlying mechanisms of action, and optimize treatment parameters before definitive conclusions can be drawn.

TRIAL REGISTRATION: irct.ir, ID: 20170702034861N8. Registered on 26/08/2019.},
}

@article {pmid41491073,
year = {2026},
author = {Wasim, R and Azmi, S and Ahmad, A and Srivastava, A},
title = {NLRP3 inflammasome and Alzheimer's disease: bridging inflammation and neurodegeneration.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41491073},
issn = {1568-5608},
abstract = {The progressive neurodegenerative disease known as Alzheimer's disease (AD) is characterized by widespread neuronal death, memory loss, and cognitive decline. The NLRP3 inflammasome has emerged as a key modulator of neuroinflammation, which is increasingly implicated in the pathophysiology of AD. In response to endogenous and pathogenic danger signals, the innate immune system's multiprotein complex known as the NLRP3 inflammasome is activated. Pyroptosis and neuroinflammatory cascades are eventually triggered by its activation, which causes caspase-1 to be cleaved and pro-inflammatory cytokines like interleukin-1β and interleukin-18 to be released. NLRP3 activation is strongly stimulated by tau aggregation and β-amyloid plaques in AD, which accelerates neuronal damage and prolongs chronic inflammation. The control and activation of inflammasomes are involved in both canonical and non-canonical pathways as well as mitochondrial dysfunction. Significantly, animal models indicate that NLRP3's therapeutic potential is highlighted by the reduction of amyloid burden and amelioration of cognitive decline that results from its inhibition or genetic deletion. Small-molecule inhibitors and natural substances that can alter NLRP3 activity have been discovered recently, providing intriguing approaches to AD treatment. Despite tremendous advancements, issues with medication selectivity and blood-brain barrier penetration still need to be resolved before these discoveries can be used in clinical settings. Comprehending the complex relationship between NLRP3 activation and Alzheimer's pathology may open the door to new, focused treatments meant to slow or stop the progression of the illness.},
}

@article {pmid41490490,
year = {2026},
author = {Wang, W and Huang, R and Lv, L and Ma, X and Li, Z and Zhang, Y and Wu, J and Wu, S and Xu, J and Hu, Y and Turck, CW and Li, H and Hu, X},
title = {Long-term effects of forty-hertz auditory stimulation as a treatment of Alzheimer's disease: Insights from an aged monkey model study.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {123},
number = {2},
pages = {e2529565123},
doi = {10.1073/pnas.2529565123},
pmid = {41490490},
issn = {1091-6490},
mesh = {Animals ; *Alzheimer Disease/therapy/pathology/cerebrospinal fluid ; Macaca mulatta ; tau Proteins/cerebrospinal fluid ; Disease Models, Animal ; Amyloid beta-Peptides/cerebrospinal fluid ; *Acoustic Stimulation/methods ; Male ; Female ; *Aging ; Humans ; Brain/pathology ; },
abstract = {Based mainly on rodents studies, forty-hertz (40-Hz) physical stimulation has been regarded as a potential noninvasive treatment for Alzheimer's disease (AD). Considering the brain differences between rodents and humans, the effects of 40-Hz physical stimulation need to be further validated using nonhuman primates before its clinical application. Here, we took advantage of a rare opportunity to expose nine aged rhesus monkeys (26 to 31 y old) to 40-Hz auditory stimulation. Given the strong correlation between cerebrospinal fluid (CSF) Aβ and Tau concentrations and corresponding AD pathology in brain parenchyma in clinical practice, we investigated the effects of 40-Hz stimulation on AD pathology by monitoring changes in CSF Aβ and Tau concentrations. Our results revealed that 7 consecutive days of 40-Hz auditory stimulation triggered a rapid and significant increase of Aβ levels by more than 200%, but no effect on Tau levels in the CSF. Additionally, we observed that the elevation of CSF Aβ levels persisted for more than 5 wk after cessation, which had not been reported in any previous studies. After this, a pathological examination of the temporal cortices of 4 of the experimental monkeys was carried out and the data demonstrated that all of them had prevalent extracellular Aβ senile plaque pathology, whereas Tau pathology was negative or very weak. These results provide a good explanation for the differences between the CSF Aβ and Tau protein levels. Together, these first-time results from monkeys suggest that 40-Hz auditory stimulation has strong potential of a noninvasive AD treatment method.},
}

Animals
*Alzheimer Disease/therapy/pathology/cerebrospinal fluid
Macaca mulatta
tau Proteins/cerebrospinal fluid
Disease Models, Animal
Amyloid beta-Peptides/cerebrospinal fluid
*Acoustic Stimulation/methods
Male
Female
*Aging
Humans
Brain/pathology

@article {pmid41490210,
year = {2026},
author = {Giuffrè, GM and Battisti, F and Tudor, AM and Lenkowicz, J and Avitabile, A and Rosati, AM and Martellacci, N and Patarnello, S and Torelli, F and Cesario, A and Marra, C},
title = {Redefining management of mild cognitive impairment and Alzheimer's disease through the shift from clinical to clinical-biological diagnosis: Insights from a single-center experience.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411461},
doi = {10.1177/13872877251411461},
pmid = {41490210},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) diagnosis has shifted from a purely clinical framework to a clinical-biological paradigm, driven by biomarker integration. This evolution is motivated by the wider availability of reliable biomarkers and the advent of disease-modifying treatments.ObjectiveTo assess changes over time in clinical characteristics, diagnostic pathways, and healthcare resource utilization in a real-world cohort of individuals with cognitive impairment attending a Memory Clinic.MethodsThis secondary data retrospective observational study analyzed two patient cohorts with newly diagnosed cognitive impairment: one from 2017-2019 and another from 2021-2023. Anonymized medical records and structured hospital data were examined using natural language processing to extract demographic and clinical information, diagnostic pathways, treatment patterns and comorbidities.ResultsThe 2021-2023 cohort was significantly younger, exhibited higher baseline Mini-Mental State Examination scores, and underwent more instrumental assessments than the 2017-2019 cohort. These findings likely reflect a shift in public awareness and attitudes toward cognitive health. AD diagnoses increased in both cohorts over time, while mild cognitive impairment diagnoses declined. The use of diagnostic combinations was more frequent in the recent cohort, in which clinical-biological diagnoses were significantly more prevalent.ConclusionsThis study provides real-world insights into the evolving landscape of cognitive impairment diagnostics and care, underscoring a shift toward earlier, biologically grounded diagnosis, supporting precision medicine in AD care. The expanded use of biomarkers reflects evolving practice standards and prepares the ground for disease-modifying therapies in AD.},
}

@article {pmid41490207,
year = {2026},
author = {Liu, Y and Su, H and Guan, T and Li, X and Dong, C and Hu, Z and Zhang, Y},
title = {Risk prediction of progression from normal cognitive function to Alzheimer's disease in elderly aged 65 and above based on deep learning methods.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251410937},
doi = {10.1177/13872877251410937},
pmid = {41490207},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a severe neurological disorder for which a complete cure is not currently available. Therefore, predicting the risk of AD in elderly individuals with normal cognitive function is crucial for early prevention, treatment, and family-provided daily care preparation.ObjectiveThis study aimed to establish a risk prediction model for the progression from normal cognitive function to AD in elderly via deep learning (DL) methods to provide a reference for clinical decision-making and the development of screening tools for the early diagnosis of AD.MethodsDeepSurv, DeepHit, and Cox models were constructed, and the consistency index (C-index), integrated Brier score (IBS), and area under the ROC curve (AUC) were used to evaluate the accuracy, calibration and discriminative power of the three prediction models.ResultsThe overall predictive ability of the model was relatively stable, with concordance indices of 0.82 (DeepSurv), 0.83 (DeepHit), and 0.81 (Cox) and IBSs of 0.08, 0.07, and 0.05, respectively. From the perspective of the C-index indicator, the consistency of the deep learning model was better than that of the Cox model.ConclusionsRisk prediction models for the progression from normal cognitive function to AD can be established using easily obtainable early-stage predictors, which are expected to be used for rapid screening of the risk of developing AD in elderly after clinical validation.},
}

@article {pmid41490027,
year = {2026},
author = {Yang, JW and Jiang, J},
title = {Association between varicella-zoster virus and Alzheimer's disease: A systematic review and meta-analysis of comprehensive evidence from infection, treatment to prevention.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411573},
doi = {10.1177/13872877251411573},
pmid = {41490027},
issn = {1875-8908},
abstract = {BackgroundThe association between varicella-zoster virus (VZV) infection and Alzheimer's disease (AD) risk has shown inconsistent results. Given difficulties in early diagnosis and limited therapeutic options for AD, identifying modifiable risk factors is significant for prevention.ObjectiveTo systematically evaluate the impact of VZV infection on AD risk and explore protective effects of antiviral treatment and vaccination.MethodsWe searched PubMed and Web of Science databases up to April 2025. The Newcastle-Ottawa Scale assessed study quality. Random-effects models were used for meta-analysis using risk ratios (RR) as the primary effect measure, with sensitivity and subgroup analyses conducted.ResultsTwenty-one studies were included. Meta-analysis showed: (1) herpes zoster patients had significantly higher AD risk (RR = 1.12, 95% CI: 1.01-1.24, p = 0.04); (2) patients receiving antiviral treatment had lower AD risk (RR = 0.55, 95% CI: 0.37-0.82, p = 0.003); (3) vaccinated individuals had lower AD risk (RR = 0.72, 95% CI: 0.68-0.78, p < 0.0001). The strongest association occurred in the >70 years age group, demonstrating age as an important effect modifier.ConclusionsThis meta-analysis provides systematic evidence supporting that VZV infection increases AD risk while confirming protective effects of antiviral treatment and vaccination. These findings support including herpes zoster vaccination in preventive healthcare for elderly populations.},
}

@article {pmid41488982,
year = {2025},
author = {Ressa, R and Ettinger, J and Chowdhury, E and Graham, L and Ndirangu, K and Mancebo, JZ and Bodnar, C},
title = {A value assessment of patient-level outcomes and productivity loss for intravenous and subcutaneous lecanemab for patients with early Alzheimer's disease.},
journal = {Journal of medical economics},
volume = {29},
number = {1},
pages = {118-134},
doi = {10.1080/13696998.2025.2609499},
pmid = {41488982},
issn = {1941-837X},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Injections, Subcutaneous ; Markov Chains ; Patient Preference ; Administration, Intravenous ; Cost-Benefit Analysis ; Caregivers ; Efficiency ; Decision Support Techniques ; },
abstract = {AIMS: Intravenous (IV) lecanemab is approved for the treatment of patients with early Alzheimer's disease (AD); a subcutaneous (SC) option may offer additional benefits. We assessed the overall value of SC treatments, and direct/indirect outcomes associated with IV and SC lecanemab.

METHODS AND MATERIALS: For the narrative review, PubMed was searched (February 2025) for studies comparing patient preferences for IV/SC treatment administration published between 2015-2025. Study eligibility was determined using patient, intervention, comparator, outcomes, and study criteria. For the decision-analytic model, a Markov model was developed with four lecanemab treatment scenarios. Scenarios one to three included IV initiation (10 mg/kg biweekly) to month 18, followed by either IV initiation continued (10 mg/kg biweekly), SC maintenance (250 mg weekly) or IV maintenance (10 mg/kg every 4 weeks). Scenario four included SC initiation (500 mg weekly) for an 18-month period, followed by SC maintenance (250 mg weekly). Outcomes were administration time/frequency; patient, caregiver, and healthcare professional time; and caregiver productivity loss.

RESULTS: Forty-three publications reported patient treatment preferences. Most (88.4%) reported that patients preferred SC over IV. Key reasons for this were time savings (n = 13/43 studies; 30.2%), convenience (n = 11/43; 25.6%), treatment frequency (n = 12/43; 27.9%). Two studies (n = 2/43; 4.7%) reported an IV preference over SC; for three studies (n = 3/43; 7.0%), treatment preference was driven by administration frequency. Decision-analytic modeling of lecanemab treatment scenarios revealed that IV initiation to IV maintenance had the lowest number of administrations, whereas SC initiation to SC maintenance had the lowest number of treatment hours and caregiver productivity losses.

LIMITATIONS: Caution must be taken when generalizing these results for all AD patients.

CONCLUSIONS: SC treatments show value as a therapeutic option. IV and SC lecanemab availability may offer benefits to patients, caregivers, and society, and improve shared decision making.},
}

Humans
*Alzheimer Disease/drug therapy
Injections, Subcutaneous
Markov Chains
Patient Preference
Administration, Intravenous
Cost-Benefit Analysis
Caregivers
Efficiency
Decision Support Techniques

@article {pmid41488470,
year = {2026},
author = {Cho, Y and Lee, J and Choi, BY and Yun, JH and Han, S and Baek, SH and Park, J and Cho, Y and Kim, HK and Kim, E and Palomera, LF and Lim, J and Jeon, Y and Im, J and Hong, JM and Kim, TK and Kim, SH and Yim, JH and Jo, DG},
title = {Ramalin Ameliorates Alzheimer's Disease Pathology by Targeting BACE1, HDAC6, and MAPK Pathways.},
journal = {MedComm},
volume = {7},
number = {1},
pages = {e70518},
pmid = {41488470},
issn = {2688-2663},
abstract = {Aberrant deposition of β-amyloid (Aβ) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating β-site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen-activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, Aβ plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed Aβ oligomer-induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease-modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease-modifying candidate with the potential to drive a breakthrough approach targeting AD pathology.},
}

@article {pmid41488323,
year = {2025},
author = {Lotlikar, MS and Zellmer, JC and Bhattacharyya, R},
title = {Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1733659},
pmid = {41488323},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.},
}

@article {pmid41487944,
year = {2026},
author = {Rus Prelog, P and Zupan, M and Gregorič Kramberger, M and Frol, S},
title = {The Concomitant Use of Selective Serotonin Reuptake Inhibitors and Anti-Amyloid Treatment in Alzheimer's Disease: Balancing Benefits and Risks.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {16},
number = {1},
pages = {1-3},
pmid = {41487944},
issn = {1664-5464},
}

@article {pmid41487496,
year = {2025},
author = {Cheng, R and Kim, J},
title = {Intranasal delivery of iron chelators and management of central nervous system disease.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1709259},
pmid = {41487496},
issn = {1663-9812},
abstract = {Brain iron dyshomeostasis plays a critical role in the pathology of multiple central nervous system (CNS) disorders, including neurodegenerative and neuropsychiatric diseases. Iron chelators such as deferoxamine (DFO) and deferiprone (DFP) have demonstrated therapeutic potential in mitigating disease progression in these conditions. However, systemic administration is hindered by poor blood-brain barrier (BBB) permeability, dose-limiting toxicity, and poor patient compliance due to frequent dosing regimens. In recent years, intranasal (IN) drug delivery has emerged as a promising strategy to bypass the BBB, providing a direct nose-to-brain delivery route via olfactory and trigeminal pathways while minimizing systemic exposure. This review provides a comprehensive summary of the current status of iron chelation therapy for CNS disorders with a focus on pharmacokinetics, efficacy, and translational potential of IN administration. While IN DFO has been extensively studied in preclinical models of Alzheimer's disease and stroke, recent developments have expanded the scope to other chelators such as DFP. We compare traditional systemic routes, including oral and intravenous, with intranasal administration, highlighting their respective advantages and limitations for CNS delivery. With ongoing advances in formulation and delivery technologies, IN iron chelators provide a promising alternative for the treatment of CNS disorders characterized by impaired iron homeostasis in the brain.},
}

@article {pmid41487012,
year = {2026},
author = {Verma, R and Bahadur, S},
title = {A Comprehensive Review of Naringin Loaded Nano Drug Delivery System in Treatment of CNS Disorders.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128407188251116030341},
pmid = {41487012},
issn = {1873-4286},
abstract = {Citrus fruits are an abundant source of the polyphenolic phytoconstituent naringenin, which belongs to the class of flavanones. NRG shows a lot of potential as a drug for treating a number of CNS disorders, such as neuroprotective activity, antiamyloidosis, antiparkinson, antialzheimer activity, and more. However, naringenin's hydrophobic nature, which results in limited absorption, limits its therapeutic potential. In this article, we provide an outline of the variety of nanocarriers employed for delivering naringenin as carriers. Some of them include solid lipid nanoparticles, liposomes, micelles, polymeric nanoparticles, nanostructured lipid carriers, nanosuspensions, and nanoemulsions, among others. These formulations of naringenin nanomedicine have been used for the potential treatment of a series of CNS disorders. Based on various research reports, it can be said that with the right nanocarriers, naringenin proves to be a promising therapeutic alternative for the treatment of several CNS ailments, including neurological diseases, Alzheimer's, Parkinson's disease, cerebral ischemia, etc. Therefore, the present manuscript highlights the various aspects of naringenin and its pharmacological activities. Further, naringenin-loaded nanocarriers have been enlisted and discussed in detail.},
}

@article {pmid41486993,
year = {2026},
author = {Cai, M and Yan, S and Sun, Y and Huo, Q and Dai, X},
title = {miRNAs: Promising Biomarkers for Alzheimer's Diagnosis and Treatment.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050427877251118111643},
pmid = {41486993},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, and chronic neuroinflammation, leading to synaptic dysfunction and cognitive decline. Current diagnostic methods rely on clinical symptoms and limited biomarkers, while available treatments only provide symptomatic relief without halting disease progression. MicroRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have emerged as crucial regulators of gene expression through post-transcriptional mechanisms and show distinct dysregulation patterns in AD patients' blood, cerebrospinal fluid (CSF), and brain tissues. Key miRNAs such as miR-132, miR-146a, miR-34a, and miR-125b demonstrate consistent alterations in expression levels, correlating with disease progression and offering potential as non-invasive diagnostic tools. This review comprehensively examines the dual role of miRNAs as diagnostic biomarkers and therapeutic targets for AD. We also provide an analysis of specific miRNA signatures in different biofluids (plasma, serum, CSF) and brain regions that correlate with disease stages, highlighting their potential for early and non-invasive diagnosis. Therapeutically, miRNAs modulate multiple AD-related pathways, including neuroinflammation via NF-κB signaling, Aβ production through BACE1 inhibition, and tau phosphorylation via GSK3β regulation. miRNAs also influence synaptic plasticity, mitochondrial function, and autophagy, presenting multifaceted opportunities for intervention. However, challenges, including miRNA heterogeneity, stability, and targeted delivery, remain critical impediments. Advances in nanocarriers, exosomal miRNAs, and viral vectors show promise in overcoming these obstacles, enabling precise miRNA modulation. In addition, we underscore the need for standardized protocols, further validation in clinical cohorts, and the development of cost-effective detection methods to translate miRNA-based approaches into practical diagnostics and therapies. By integrating miRNA biomarkers with existing diagnostic tools and exploring combinatorial therapeutic strategies, researchers can harness the potential of miRNAs to revolutionize AD intervention, paving the way for early detection and effective treatment of this devastating disease.},
}

@article {pmid41486988,
year = {2026},
author = {Ranjbari, F and Dadkhah, M and Pirdel, Z and Fathi, F},
title = {Margatoxin Peptide: Preparation and the Potential Use for Biological Applications in Cancer and Neurological Disorders.},
journal = {Protein and peptide letters},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298665415268251024053300},
pmid = {41486988},
issn = {1875-5305},
abstract = {Scorpion venom compounds are known to contain nucleotides, polypeptides, mucoproteins, lipids, biogenic amines, and other unidentified macromolecules. Several peptides in scorpion fluids have demonstrated a wide range of biological activities with strong specificity for their targeted sites. Margatoxin, isolated from the venom of the scorpion, exhibits desirable properties, including high selectivity, good permeability, and stability in cancer cells, which can be achieved at picomolar doses, thereby blocking voltage-gated K+ channels. This narrative review consolidates results from an extensive literature search conducted in major electronic databases up to September 2024. Important studies were identified using keywords associated with scorpion venom peptides, Kv1.3 channels, cancer treatment, and neurodegenerative disorders. The amino acids that make up Margatoxin have an effective molecular function in blocking voltage-gated K+ channels 1.3. Due to the abnormally high expression of voltage-gated K[7] channel 1.3 in various types of cancers, blockers of this channel can inhibit apoptosis, metabolic changes, tumor angiogenesis, invasion, and migration. On the other hand, these channel blockers have emerged as a promising therapeutic approach for neurological disorders, such as Alzheimer's and Parkinson's diseases. The strong efficacy and targeted action of margatoxin further position it as a promising drug candidate. As the number of individuals affected by cancer and neurological conditions continues to rise, research into scorpion venom peptides like margatoxin may lead to innovative therapeutic options for future treatments.},
}

@article {pmid41486697,
year = {2026},
author = {Pan, H and Cheng, X and Zhang, J and Hou, K and Murray, KA and Manglani, K and Zhu, C and Hsu, HK and Mekkittikul, M and Halladay, T and Mirbaha, H and Elezi, G and Abskharon, R and Sawaya, MR and Bombino, A and Williams, CK and DeTure, M and Dickson, DW and Vinters, HV and Whitelegge, JP and Harran, PG and Cole, GM and Frautschy, SA and Eisenberg, DS},
title = {In Vitro and In Vivo Evaluation of Small-Molecule Disassemblers of Pathological Tau Fibrils.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00940},
pmid = {41486697},
issn = {1948-7193},
abstract = {Aggregation of the microtubule-binding protein tau is the histopathological hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, which are collectively known as tauopathies. Tau aggregation in AD patients is correlated with neuron loss, brain atrophy, and cognitive decline, and pro-aggregation tau mutations are sufficient to cause neurodegeneration and dementia in humans and tauopathy model mice. Thus, reversing tau aggregation is a potential therapeutic avenue for AD. In a previous study, we discovered CNS-11, a small molecule that disaggregates AD patient brain-extracted tau fibrils in vitro. In this study, we identify two chemical analogs of CNS-11, named CNS-11D and CNS-11G, that disaggregate AD patient brain-extracted tau fibrils and prevent seeding in a tau aggregation cell culture model. We also demonstrate that 8 weeks of treatment with either CNS-11D or CNS-11G reduces levels of insoluble tau in a mouse model of tauopathy. Our work defines the properties of two small molecules that diminish aggregation of tau in vivo and provides further support for structure-based methods to target tau for treatment of AD.},
}

@article {pmid41486173,
year = {2026},
author = {Silva-Llanes, I and Smith, LA and Abdelkader-Guillén, A and Jiménez-Villegas, J and Sarrió, D and Moreno-Bueno, G and Lastres-Becker, I},
title = {GASDERMIN D-mediated pyroptosis as a therapeutic target in TAU-dependent frontotemporal dementia mouse model.},
journal = {Journal of biomedical science},
volume = {33},
number = {1},
pages = {6},
pmid = {41486173},
issn = {1423-0127},
support = {PID2022-136854OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2022-137065OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; CB16/12/00295//Centro de Investigación Biomédica en Red de Cáncer/ ; CB06/05/0089//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; },
mesh = {Animals ; *Pyroptosis/genetics ; Mice ; *tau Proteins/metabolism/genetics ; Disease Models, Animal ; Humans ; *Phosphate-Binding Proteins/metabolism/genetics ; Mice, Transgenic ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism/drug therapy/pathology ; Male ; Female ; Alzheimer Disease/genetics ; Mice, Inbred C57BL ; Aged ; Hippocampus/metabolism ; Gasdermins ; },
abstract = {BACKGROUND: Recent research has revealed a strong connection between neuroinflammation and TAU protein-related neurodegeneration. A key discovery shows that the NLRP3 inflammasome, when activated, can significantly impact TAU pathology and subsequent neuronal death. This process involves pyroptosis, a lytic form of programmed cell death driven by inflammasome activation, leading to GASDERMIN D (GSDMD) cleavage and the subsequent release of inflammatory molecules IL-1β and IL-18. In this study, we explore the role of pyroptosis and GSDMD in Alzheimer's disease (AD) and tauopathy models, focusing on the TAU-induced neuroinflammatory process and its correlation with synaptic plasticity loss.

METHODS: Hippocampal tissue from AD patients at Braak stage II-III has been analyzed using qPCR to assess pyroptosis-related gene expression. To determine the role of TAU in pyroptosis and neuroinflammation, we used two different models: one based on intracerebral injection of an adeno-associated virus that specifically overexpresses TAU in the neurons of the hippocampus (AAV-TAU[P301L]), and a transgenic mouse model Tg-TAU[P301S] at 8 and 10 months of age. Gene expression, protein levels, and neuroinflammation markers were evaluated using qPCR and immunofluorescence. Additionally, both genetic (GSDMD-deficient mice) and pharmacological (dimethyl fumarate, DMF) interventions targeting pyroptosis have been explored to assess their impact on neuroinflammation and synaptic plasticity.

RESULTS: AD patients exhibited increased expression of pyroptosis-related genes, supporting the involvement of pyroptosis in neurodegeneration. Furthermore, TAU overexpression induced pyroptosis in both mouse models, and GSDMD protein levels increased alongside reactive microglial morphology. Our data supports that TAU-induced neuroinflammation correlated with synaptic plasticity impairment. GSDMD deficiency significantly reduced pyroptosis-related markers associated to TAU, but unexpectedly worsened synaptic plasticity deficits, suggesting GSDMD may play a dual role in inflammation and synaptic function. Finally, we showed that DMF treatment suppressed pyroptosis gene expression, reduced GSDMD levels, and alleviated neuroinflammation, correlating with improved synaptic marker expression.

CONCLUSION: Our findings demonstrate that TAU-induced pyroptosis contributes to neuroinflammation and synaptic dysfunction. While GSDMD inhibition mitigates inflammation, its absence exacerbates synaptic impairment, highlighting its complex role in tauopathies. Our results indicate that DMF treatment could offer a promising therapeutic avenue to modulate pyroptosis and neuroinflammation, and restore synaptic integrity in tauopathies.},
}

Animals
*Pyroptosis/genetics
Mice
*tau Proteins/metabolism/genetics
Disease Models, Animal
Humans
*Phosphate-Binding Proteins/metabolism/genetics
Mice, Transgenic
*Intracellular Signaling Peptides and Proteins/metabolism/genetics
*Frontotemporal Dementia/genetics/metabolism/drug therapy/pathology
Male
Female
Alzheimer Disease/genetics
Mice, Inbred C57BL
Aged
Hippocampus/metabolism
Gasdermins

@article {pmid41485615,
year = {2026},
author = {Pariya Gholizadeh Dangheralou, SK and Khazaeifard, F and Mehr, SR and Mansouri, SM and Rad, NR and Abbasi-Maleki, S},
title = {Evaluation of neurobiochemical and behavioral responses to carvone nanoemulsion: A neuroprotective approach for Alzheimer's disease-associated dementia in a rat model.},
journal = {Brain research},
volume = {},
number = {},
pages = {150143},
doi = {10.1016/j.brainres.2026.150143},
pmid = {41485615},
issn = {1872-6240},
abstract = {BACKGROUND: Antioxidant supplements have emerged as promising strategies to mitigate the impact of Alzheimer's disease (AD) and associated dementia. We explored the neuroprotective potential of Carvone nanoemulsion (CANO) using a rat model of AD-associated dementia.

METHOD: Our experimental groups comprised non-AD control rats (CON), untreated AD rats (AD), and AD rats treated with CANO at two different dosages: 40 mg/kg (CANO40) and 80 mg/kg (CANO80). We assessed various behavioral parameters, malondialdehyde (MDA) and brain-derived neurotrophic factor (BDNF) levels,ferric-reducing ability of plasma (FRAP).

RESULTS: AD induction caused a significant reduction in step-through latency (P < 0.001), center time (P < 0.001), the number of visits (P < 0.001), and total distance traveled (P < 0.001), time spent in open arms (P < 0.001), and both FRAP (P < 0.001) and BDNF levels (P < 0.001) in comparison to the CON group, while elevating escape latency, time in target zone and platform location latency, and MDA levels (P < 0.001). Treatment with CANO, particularly at the CANO80 dosage, significantly improved these parameters compared to the AD group, resulting in decreased time in the target zone (P < 0.001), escape latency (P < 0.001), and platform location latency (P < 0.001) and higher FRAP (P < 0.05) and BDNF levels (P < 0.05), along with decreased MDA levels (P < 0.05).

CONCLUSION: CANO, especially at the 80 mg/kg dosage, shows promise in alleviating symptoms associated with AD-associated dementia. However, further research is warranted to validate and expand upon these findings.},
}

@article {pmid41485573,
year = {2026},
author = {Pi, G and Zhang, L and Lei, H and Zhong, T and Zhang, F and Lu, Y and Qiu, X and Qi, Y and Dong, Y and Zhu, R and Qin, Q and Wang, J and Sarapultsev, A and Luo, S and Cheng, X and Yang, Y and Wang, JZ and Hu, D},
title = {Ursolic acid reduces Aβ-driven aggression via Gab1-mediated autophagy and dorsal hippocampal circuit modulation in Alzheimer's disease.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2025.12.054},
pmid = {41485573},
issn = {2090-1224},
abstract = {INTRODUCTION: Aggression is one of the most debilitating neuropsychiatric symptoms in Alzheimer's disease (AD), posing significant challenges for both patients and caregivers. However, the underlying mechanism remains unclear, and effective therapeutic strategies are lacking.

OBJECTIVES: This study aimed to investigate the neural circuit mechanisms underlying amyloid-beta (Aβ)-driven aggression in AD and explore the therapeutic potential of ursolic acid (UA) in alleviating this behavior.

METHODS: A combination of virus tracing, electrophysiological recording, in vivo Ca2 + recording, and a aggressive behavior test was utilized to investigate the neural circuit vulnerable to Aβ-driven aggression. optogenetic or chemogenetic manipulation was used to identify the regulation of the neural circuit on aggressive behavior. Proteomics and molecular targeting were employed to explore the underlying mechanisms of Aβ-driven aggression and evaluate UA's effects.

RESULTS: We identified that Aβ accumulation drove hyperexcitability of dorsal hippocampal CA3 (dCA3) neurons projecting to the dorsal lateral septum (dLS), thereby triggering aggressive behavior in the 5xFAD mouse model. Optogenetic activation of the dCA3-dLS circuit in wild-type mice induced aggression, whereas either optogenetic or chemogenetic inhibition of this projection alleviated aggression in 5xFAD animals. Proteomic profiling of dCA3 tissue identified Grb2-associated binding protein 1 (Gab1) as a key mediator upregulated in 5xFAD mice and normalized by ursolic acid (UA) treatment. UA reduced Aβ plaque burden, restored autophagic flux (increasing LC3B-II and decreasing p62), and suppressed dCA3-dLS circuit hyperactivity, resulting in durable attenuation of aggressive behavior. Viral knockdown of Gab1 in dCA3 mimicked UA's effects on autophagy, Aβ clearance, circuit excitability, and aggression, whereas Gab1 overexpression blocked UA's benefits.

CONCLUSION: Together, these results define a novel Gab1-dependent autophagy-circuit mechanism for Aβ-induced aggression and establish UA as a promising candidate for alleviating neuropsychiatric symptoms in AD.},
}

@article {pmid41485354,
year = {2025},
author = {Lin, X and Tang, L and Hu, Z},
title = {Causal relationship between tractography-based brain white matter structural connectome and risk of psychiatric disorders: A bidirectional Mendelian randomization study.},
journal = {Psychiatry research. Neuroimaging},
volume = {357},
number = {},
pages = {112131},
doi = {10.1016/j.pscychresns.2025.112131},
pmid = {41485354},
issn = {1872-7506},
abstract = {AIM: This study sought to explore the causal link between 206 tractography-derived white matter connectivity metrics in the brain and the risk of nine psychiatric disorders, employing a bidirectional two-sample Mendelian randomization (MR) approach.

METHOD: Summary datasets of 9 psychiatric disorders including anxiety disorder, Alzheimer's disease (AD), major depressive disorder (MDD), autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia, Tourette syndrome(TS), attention-deficit hyperactivity disorder (ADHD), and cannabis use disorder (CUD) were used. MR analyses were performed using the inverse variance weighted (IVW), weighted median, MR-Egger, MR-PRESSO, and MR-robust adjusted profile score (MR-RAPS) method.

RESULTS: Forward MR analysis showed that the left-hemisphere dorsal attention network to the right-hemisphere limbic network connectome was causally associated with a 32 % higher risk of anxiety disorder [odds ratio(OR) = 1.32; 95 % confidence interval (CI): 1.16, 1.51). Reverse MR analysis indicated that AD was associated with a 7 % higher risk for the left-hemisphere limbic network to the right-hemisphere control network connectome(OR = 1.07; 95 % CI: 1.03, 1.10).

CONCLUSIONS: Our MR analysis reveals causal relationships between brain white matter structural connectivity and psychiatric disorders, advancing our knowledge of the neural mechanisms that contribute to psychiatric disorders and providing evidence for targeted interventions in psychiatric treatment.},
}

@article {pmid41485137,
year = {2026},
author = {Zhu, Z and Steward, A and Dehsarvi, A and Roemer-Cassiano, SN and Dewenter, A and Biel, D and Hirsch, F and Frontzkowski, L and Pescoller, J and Klonowski, M and Gnörich, J and Pontecorvo, MJ and Shcherbinin, S and Schöll, M and Buckley, R and Ossenkoppele, R and Xie, F and Guo, T and , and Höglinger, G and Brendel, M and Franzmeier, N},
title = {Defining patient-centered amyloid PET thresholds for the onset of tauopathy in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71064},
pmid = {41485137},
issn = {1552-5279},
support = {AARG-22-973496/ALZ/Alzheimer's Association/United States ; //Gerhard and Ilse Schick Foundation/ ; BMBF 01KU2203//ERAPerMed/ ; },
mesh = {Humans ; *Positron-Emission Tomography ; Male ; *Alzheimer Disease/diagnostic imaging/metabolism ; Female ; *Tauopathies/diagnostic imaging/metabolism ; Aged ; tau Proteins/metabolism ; Aged, 80 and over ; *Amyloid/metabolism ; Sex Factors ; Age Factors ; Brain/diagnostic imaging/metabolism ; Carbolines ; },
abstract = {INTRODUCTION: Amyloid-induced tauopathy drives clinical decline in Alzheimer's disease (AD). Because age and sex shape tau trajectories, defining patient-centered amyloid thresholds for tauopathy onset could facilitate pre-tauopathy AD identification and aid treatment decisions and prognosis.

METHODS: By including two samples (Alzheimer's Disease Neuroimaging Initiative [ADNI, n = 301]; and 18F-AV-1451-A05 [A05, n = 143]), we explored whether age and sex affect tauopathy transition and determined patient-centered amyloid positron emission tomography (PET) thresholds that mark tauopathy onset.

RESULTS: We found a consistent amyloid PET × age interaction on global tau PET increase in men (ADNI/A05: p = 0.0078/0.018), with younger men showing faster amyloid-associated tau accumulation. We then established patient-centered, amyloid PET-inferred tauopathy transition cut-offs. Women reached this transition at lower amyloid PET levels, and these cutoffs predicted both earlier onset and accelerated cognitive decline (p < 0.001).

DISCUSSION: This study highlights the effect of age and sex on the amyloid-to-tauopathy transition, establishes patient-centered amyloid PET thresholds for tauopathy onset, and links these thresholds to accelerated cognitive decline.

HIGHLIGHTS: Younger age is related to faster amyloid-related tau accumulation in men. We defined a series of amyloid positron emission tomography (PET) thresholds to enable patient-centered inference of amyloid-related tauopathy. Crossing the amyloid PET-defined tauopathy phase is associated with more progressive tau deposition and cognitive decline.},
}

Humans
*Positron-Emission Tomography
Male
*Alzheimer Disease/diagnostic imaging/metabolism
Female
*Tauopathies/diagnostic imaging/metabolism
Aged
tau Proteins/metabolism
Aged, 80 and over
*Amyloid/metabolism
Sex Factors
Age Factors
Brain/diagnostic imaging/metabolism
Carbolines

@article {pmid41484932,
year = {2026},
author = {Nitzan, K and Bentulila, Z and Bregman-Yemini, N and Ayalon, N and David, D and Break, E and Sarne, Y and Doron, R},
title = {Sex-dependent effects of ultra-low-dose-THC preventive treatment on neuroinflammation and cognitive decline in 5xFAD mice.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-025-00815-3},
pmid = {41484932},
issn = {2042-6410},
support = {3-2021-2022b//National Institute for Psychobiology in Israel, Hebrew University of Jerusalem/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) remains the most prevalent cause of dementia, yet no existing treatment effectively prevents its onset. Current therapies primarily aim to slow disease progression or manage symptoms, leaving a critical gap in preventive strategies. Recent findings suggest that ultra-low-dose tetrahydrocannabinol (ULD-THC) may exert neuroprotective effects without the adverse consequences associated with chronic THC use. This study investigates whether preventive ULD-THC treatment can mitigate neuroinflammation and early cognitive decline in the 5xFAD mouse model of AD, with a specific focus on sex differences in treatment response.

METHODS: Male and female 5xFAD mice received monthly ULD-THC injections from 3 to 5 months of age, before significant pathology emerged. At 6 months, behavioral assessments were conducted, followed by molecular analyses of hippocampal and prefrontal cortex (PFC) tissue.

RESULTS: Results indicated that ULD-THC attuned AD-related cognitive decline in both males and females, with sex-specific neuroinflammatory responses. Males exhibited reduced hippocampal inflammation, whereas females showed reduced inflammation in the PFC, suggesting distinct neuroprotective mechanisms across sexes.

CONCLUSIONS: These findings highlight ULD-THC's potential as a preventive strategy for AD, emphasizing the importance of sex-dependent therapeutic approaches. By attenuating neuroinflammatory processes before cognitive deficits fully manifest, ULD-THC offers a novel, biologically targeted approach to AD prevention. Future research should explore its long-term efficacy and translational potential in clinical settings.},
}

@article {pmid41484644,
year = {2026},
author = {Kim, T and Hong, YJ and Kim, M and Bae, Y and Lee, SB and Kim, SH and Lee, MA and Ko, E and Park, JW and Yang, DW},
title = {Impact of dose and compliance of antidementia medications on long-term outcomes in Alzheimer's disease: a nationwide real-world study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-025-01942-0},
pmid = {41484644},
issn = {1758-9193},
abstract = {BACKGROUND: Antidementia medications are widely prescribed for Alzheimer's disease (AD), but their long-term real-world effectiveness remains uncertain. This study investigated whether long-term outcomes differ according to medication dosage and compliance using nationwide data.

METHODS: Data from the Korean National Health Insurance Service (NHIS) covering 47 million individuals were analyzed. Prescription data for acetylcholinesterase inhibitors and memantine were analyzed for dosage and compliance. Among 1,704,547 dementia cases (2010-2016), 466,773 patients with clinically diagnosed AD were included. Medication dosage and compliance during the first three years after diagnosis were categorized to define optimal versus suboptimal treatment. Clinical outcomes included progression to moderate to severe dementia, institutionalization, and mortality. Multivariable logistic regression identified factors associated with outcomes.

RESULTS: Patients who maintained optimal dosage and compliance during the first three years after diagnosis showed a lower rate of progression to moderate to severe dementia than those receiving suboptimal treatments consistently across all classification criteria. Regression analyses revealed that optimal compliance and dosage were strongly associated with reduced progression (OR 0.807 and 0.704, respectively; p < 0.0001) and early mortality within five years. In contrast, mortality and institutionalization rates were not significantly different between groups except that mortality within five years.

CONCLUSIONS: Both medication dosage and persistence were independently associated with better long-term outcomes in AD. Maintaining optimal treatment during the early disease period may delay disease progression and improve survival within five years. This nationwide real-world study provides robust evidence supporting the importance of sustained, adequate antidementia therapy in clinical practice.},
}

@article {pmid41484454,
year = {2026},
author = {Ibrahim, M and Khalil, AM and Attia, H and Alseekh, S and Mohamed, AF and El-Yamany, MF},
title = {Gut Microbiome-Sphingolipid Metabolism-Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {3},
pmid = {41484454},
issn = {1557-1904},
mesh = {Animals ; *Sphingomyelin Phosphodiesterase/antagonists & inhibitors/metabolism ; *Gastrointestinal Microbiome/drug effects/physiology ; Mice ; *Amitriptyline/pharmacology/therapeutic use ; Mice, Transgenic ; *Tauopathies/metabolism/drug therapy ; *Brain/drug effects/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Sphingolipids/metabolism ; Disease Models, Animal ; Male ; Mice, Inbred C57BL ; },
abstract = {Tauopathies are neurodegenerative diseases characterized by accumulation of hyperphosphorylated tau protein (P-tau). The gut microbiota (GM) is symbiotic with the host and altered in neurodegenerative diseases. Amitriptyline (AMI) is a functional inhibitor of acid sphingomyelinase (ASM) which is abnormally highly expressed in brains of Alzheimer patients. Little data is known about the role of colonic ASM in management of tauopathy. Therefore, the aim of this study was to investigate the role of AMI on reversing gut dysbiosis, ceramide levels, colonic inflammation and intestinal barrier disruption in tauopathy through the bidirectional gut-brain axis. P301S transgenic mice were administered AMI for 35 days. Colonic ASM, ceramides, inflammation and membrane integrity were assessed besides fecal microbiome analysis and serum lipopolysaccharides to assess intestinal membrane disruption. Levels of hippocampal P-tau, protein phosphatase 2 A and neurogenesis were assessed along with cognitive behavior. AMI treatment significantly reduced colonic ASM, ceramide levels, increased abundance of Harryflintia, Dubosiella, and Parasutterella and decreased abundance of Lactobacillus, Lachnoclostridium, Oscillibacter, Oscillospiracea UCG-003, Colidextribacter, Roseburia, Butyricicoccus, and Sphingomondales. In contrast, P301S mice displayed an altered GM profile with enriched Firmicutes and Clostridia, and low proportions of Bacteroidota- a phylum associated with intestinal barrier protection-, and Ruminococcaceae. Also, AMI treatment decreased inflammation and restored colonic membrane integrity with subsequent decrease in serum lipopolysaccharides, P-tau in hippocampus and improvement in cognitive behaviour and neurogenesis. The current results indicate that AMI has neuroprotective effects against tauopathy through modulation of ASM activity, associated ceramide levels, GM composition, colonic inflammation and membrane integrity through bidirectional gut-brain axis.},
}

Animals
*Sphingomyelin Phosphodiesterase/antagonists & inhibitors/metabolism
*Gastrointestinal Microbiome/drug effects/physiology
Mice
*Amitriptyline/pharmacology/therapeutic use
Mice, Transgenic
*Tauopathies/metabolism/drug therapy
*Brain/drug effects/metabolism
*Neuroprotective Agents/pharmacology/therapeutic use
*Sphingolipids/metabolism
Disease Models, Animal
Male
Mice, Inbred C57BL

@article {pmid41484306,
year = {2026},
author = {Huang, H and Wu, J and Fang, Z and Wang, Y and Xie, J and Guan, Y},
title = {Recent Advances of the Role of Dl-3-n-Butylphthalide in the Treatment of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {340},
pmid = {41484306},
issn = {1559-1182},
support = {202510159035//Innovation and Entrepreneurship Training Program for China Medical University Students/ ; },
mesh = {Humans ; *Benzofurans/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting approximately 55.2 million individuals globally, with complex pathogenesis involving amyloid-β (Aβ) aggregation, tau pathology, neuroinflammation, oxidative stress, and synaptic dysfunction. Current treatments offer only symptomatic relief without halting disease progression. Dl-3-n-butylphthalide (NBP), a small-molecule compound originally derived from celery seeds, has emerged as a promising multi-target therapeutic candidate for AD. Preclinical studies demonstrate that NBP exerts its therapeutic effects in AD by alleviating oxidative stress, enhancing superoxide dismutase (SOD) and glutathione activities, suppressing neuroinflammation by inhibiting NLRP3 inflammasome activation and pro-inflammatory cytokine release (e.g., IL-1β, TNF-α), reducing Aβ deposition and tau hyperphosphorylation, promoting autophagy, and improving synaptic plasticity. A meta-analysis of six trials (n = 851) confirmed that NBP improves Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores with a favorable safety profile, primarily mild gastrointestinal symptoms and transient liver enzyme elevations. This review systematically summarizes recent advances in NBP research, integrating both preclinical mechanisms and clinical evidence, and highlights its potential as a novel multi-target strategy for AD treatment. Further large-scale, long-term trials are warranted to validate its efficacy and explore optimized delivery systems and combination therapies.},
}

Humans
*Benzofurans/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism
Animals
Oxidative Stress/drug effects

@article {pmid41483724,
year = {2025},
author = {Strain, JF and Rahmani, M and Phuah, CL and Dierker, D and Luo, J and Owen, C and Vlassenko, AG and Jafri, H and Bourgeat, P and Fripp, J and Jin, L and Moulder, K and Benzinger, T and Xiong, C and Lee, JM and Weiner, M and Masters, CL and Morris, JC and Womack, K and Goyal, MS and , },
title = {Regional growth rates of white matter hyperintensities are associated with beta-amyloid burden.},
journal = {Neurobiology of aging},
volume = {160},
number = {},
pages = {22-32},
doi = {10.1016/j.neurobiolaging.2025.12.006},
pmid = {41483724},
issn = {1558-1497},
abstract = {There is increasing evidence for an association between white matter hyperintensities (WMH) and brain beta-amyloid deposition. How WMH are longitudinally associated with brain beta-amyloid burden requires further investigation, particularly with respect to co-existent vascular risk factors and differences across white matter regions. We measured WMH on MRI and vascular risk factors in a combined neuroimaging data set of cognitively normal and individuals with dementia comprised of the ADNI, AIBL and OASIS3 studies, which includes harmonized centiloid estimates of beta-amyloid burden from PET imaging. WMH were measured using the TrUE-Net algorithm. Vascular risk factors were extracted from provided clinical data and used to calculate individual revised Framingham Stroke Risk Profile (FSRP) scores. Linear mixed effects modelling was used to determine the relationship between the growth rate of WMH and baseline beta-amyloid burden, controlling for age, sex, APOE4 status, and vascular risk factors. 1243 participants [49 % female, mean age 71.7 y (SD 7.6 y)] had at least 3 brain MRIs. Linear mixed models demonstrate robust independent cross-sectional relationships between WMH and baseline beta-amyloid burden (beta coefficient=0.27, p < 0.001), age (beta coefficient=0.04, p < 0.001) and vascular risk factors (beta coefficient=0.25, p < 0.001). Growth rates of WMH increased with baseline beta-amyloid burden (slope=0.021, p < 0.001) and decreased with anti-hypertensive medications (slope=-0.019, p = 0.002), above and beyond age, APOE4 status, and other vascular risk factors. The longitudinal association for beta-amyloid burden persisted in a similar analysis for parietal WM. Our study suggests that in Alzheimer disease research cohorts, WMH progression is associated with age and beta-amyloid burden, particularly in parietal white matter, and slowed by anti-hypertensive treatment.},
}

@article {pmid41482856,
year = {2026},
author = {Kalita, R and Sarma, A and Baruah, H and Zaman, A and Goswami, D},
title = {Nose to Brain Delivery of Curcumin Loaded Therapeutic Nanostructures for Neurodegenerative Diseases.},
journal = {Biopharmaceutics & drug disposition},
volume = {},
number = {},
pages = {},
doi = {10.1002/bdd.70021},
pmid = {41482856},
issn = {1099-081X},
abstract = {Neurodegenerative diseases are progressive disorders that damage and eventually kill neurons in the central nervous system (CNS). In recent years, various research has been done on reliable and effective treatment methods for the most common neurodegenerative diseases such as Parkinson's, Alzheimer, and Migraine diseases. Different neurodegenerative disorders such as Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic, Lewy body disease can be treated by curcumin, which is a strong antioxidant polyphenol with neuroprotective and anti-amyloid properties. However, Blood-brain barrier (BBB) and blood cerebrospinal fluid barrier restricts the permeation of curcumin to the brain leads poor distribution of the drug in brain tissue. The intranasal pathway holds promise for enhancing the treatment of CNS disorders since it bypasses the BBB and increases the brain bioavailability of drug. As nanotechnology continues to improve, research on the delivery of drug through intranasal route has grown significantly in last 10 years. Several nanocarriers have been developed such as nano-emulsions, microspheres, dendrimers, liposomes, carbon-based nanoformulation, and nanoparticles to deliver curcumin to the brain via intranasal route for the treatment of neurodegenerative diseases. This study provided a thorough analysis of several curcumin nano-formulations used in intranasal pathway as a novel treatment for neurodegenerative diseases.},
}

@article {pmid41482153,
year = {2025},
author = {Yan, Y and Su, J and Xie, M and Kong, Y and Wang, C and Yuan, G and Fang, Y and Hwang, K and Kim, CY and Han, H and Zhang, Z},
title = {Low Intensity Ultrasound-facilitated exosome delivery promotes hippocampal neurogenesis in Alzheimer's disease.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {103015},
doi = {10.1016/j.brs.2025.103015},
pmid = {41482153},
issn = {1876-4754},
abstract = {BACKGROUND: Low-intensity ultrasound (LIUS) and human adipose-tissue mesenchymal stem cell-derived exosomes (hADSC-Exos) have shown neuroprotective potential, but their combined effects in Alzheimer's disease (AD) remain unclear.

OBJECTIVE: To evaluate the safety and efficacy of intranasal hADSC-Exos alone or combined with LIUS in APP/PS1 mice, and explore underlying molecular mechanisms.

METHODS: Female APP/PS1 mice (30 weeks) were randomized into five groups (n=6). Treatments included intranasal hADSC-Exos, LIUS, or both for 2 months. Behavioral tests, histology, and hippocampal RNA-seq were performed.

RESULTS: LIUS enhanced Exo uptake in HT22 cells by ∼8% without toxicity. Combined treatment improved learning and memory (escape latency ↓45 s→20 s; P<0.01), increased neurogenesis markers (GFAP/SOX2, DCX, Ki67), and reduced amyloid and microglial activation. RNA-seq identified 93 specific DEGs in the combination group, with enrichment in synaptic and mitochondrial pathways. Fos and Kcnj13 were top DEGs and both downregulated after therapy (P<0.05).

CONCLUSIONS: Intranasal hADSC-Exos combined with LIUS is safe, enhances brain delivery, and synergistically improves cognition and neurogenesis in AD mice. The Fos-Kcnj13 axis may mediate these effects, suggesting a promising noninvasive therapeutic strategy.},
}

@article {pmid41482111,
year = {2025},
author = {Zheng, R and Liu, X and Liao, Z and Wan, R and Qiu, G and Li, M and Tang, C and Zhou, R and Song, J},
title = {Electroacupuncture ameliorates tau-driven cognitive decline by modulating NF-κB/NLRP3 inflammasome signaling in P301S mice.},
journal = {Experimental neurology},
volume = {398},
number = {},
pages = {115637},
doi = {10.1016/j.expneurol.2025.115637},
pmid = {41482111},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) progression is driven by a vicious cycle wherein pathological Tau hyperphosphorylation promotes microglial activation and NF-κB/NLRP3 inflammasome signaling, leading to excessive secretion of proinflammatory cytokines that reciprocally exacerbate Tau pathology. While pharmacological NLRP3 inhibitors hold therapeutic potential for AD, critical barriers-including poor blood-brain barrier penetration, suboptimal target selectivity, and safety concerns-persist. This study investigated whether electroacupuncture (EA), a non-pharmacological neuromodulatory approach, could disrupt this Tau-inflammasome cycle. Using P301S Tau transgenic mice, two EA regimens were tested at the GV20 (Baihui) acupoint: 6-month-old mice receiving a 1-month EA intervention, and 6-month-old mice undergoing a prolonged 3-month EA intervention. Cognitive function was evaluated via Y-maze, novel object recognition (NOR), and Morris water maze (MWM) tests, while corticospinal function was assessed using tail-suspension limb-clasping scoring. Hippocampal Tau pathology and inflammatory signaling were analyzed by Western blot and immunohistochemistry, targeting total Tau, phosphorylated Tau, NF-κB, NLRP3, caspase-1, IL-1β, IL-18, TNF-α, and microglial morphology. Short-term (1-month) EA treatment significantly improved spatial working memory and recognition memory. Mechanistically, EA reduced p-Tau levels, suppressed NF-κB activation (decreased p-P65/P65 ratio), downregulated NLRP3 inflammasome components (NLRP3, cleaved caspase-1) and proinflammatory cytokines (IL-1β, IL-18 and TNF-α), and mitigated microglial hyperactivation. Importantly, long-term (3-month) EA treatment persistently suppressed p-Tau accumulation and neuroinflammation, thereby consolidating cognitive benefits even in P301S mice with severe corticospinal dysfunction. These findings establish EA as a multi-targeted immunomodulatory strategy that attenuates Tau-driven neuroinflammation through the TNF-α/NF-κB/NLRP3 signaling axis, highlighting its potential as a safe, non-pharmacological adjunct or alternative therapy for AD and related tauopathies.},
}

@article {pmid41482107,
year = {2025},
author = {Chen, X and Yao, H and Ma, S and Zhu, H and Xu, Y and Zhu, Y and Ying, Y and Wang, L and Zhang, Q and Zheng, C and Zhou, Y and Tong, Z and Huang, K and Shentu, Y},
title = {FGF22/FGFR2/YAP modulates ferroptosis to suppress neurodegeneration and cognitive impairment in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {398},
number = {},
pages = {115630},
doi = {10.1016/j.expneurol.2025.115630},
pmid = {41482107},
issn = {1090-2430},
abstract = {Ferroptosis, a programmed cell death triggered by iron accumulation and lipid peroxidation, has been increasingly recognized as a critical mechanism underlying neurodegenerative processes, including Alzheimer's disease (AD). The mechanosensitive regulator YAP is implicated in AD progression and ferroptosis. Here we confirmed that FGF22, a fibroblast growth factor, amelitorated cognitive deficits in β-Amyloid (1-42) (Aβ1-42) treated AD model mice through the FGFR2/YAP pathway, which was further ascertained by various biochemical analyses. Additionally, FGF22 treatment effectively reduced ferroptosis and neuronal apoptosis, thereby attenuating synaptic impairments and neuronal injury in the AD model mice and Aβ1-42-exposed HT22 cells. Collectively, the data presented herein implicate FGF22 as a potential neuroprotective agent in AD models, with its efficacy likely mediated through engaging of the FGFR2/YAP signaling axis.},
}

@article {pmid41481960,
year = {2026},
author = {Fazal, F and Dar, NJ and Ahamad, S and Khan, S and Bano, N and Saha, S and Nazir, A and Bhat, SA},
title = {cGAS-STING signaling in Alzheimer's disease: Microglial mechanisms and therapeutic opportunities.},
journal = {Molecular aspects of medicine},
volume = {107},
number = {},
pages = {101444},
doi = {10.1016/j.mam.2025.101444},
pmid = {41481960},
issn = {1872-9452},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a neuroinflammatory disorder driven by microglial dysfunction. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a critical role in neuroinflammation and has been strongly implicated in the pathology of AD. Chronic activation of cGAS-STING contributes to neurodegeneration by driving persistent type I interferon release and excessive pro-inflammatory cytokine production. However, the pathway exhibits context-dependent effects. Transient activation promotes antiviral defense, autophagy, and cellular quality control in the central nervous system. Sustained engagement exacerbates neuroinflammation and synaptic loss. Preclinical studies demonstrate that pharmacological inhibitors (such as NR, TSG, H-151, TDI-6750, TDI-8246) mitigate amyloid beta and tau pathology, attenuate microglial reactivity, and enhance cognitive outcomes. Yet, its essential physiological roles, including antimicrobial immunity and autophagy regulation, pose challenges for therapeutic targeting. This potentially disrupts neuroimmune homeostasis. In this review, we highlight the role of cGAS-STING in AD and explore its potential as a therapeutic target using small-molecule drug candidates. Despite these promising findings, challenges remain, including optimizing blood-brain barrier (BBB) penetration, ensuring immune specificity, and addressing long-term safety concerns. Due to these challenges, no cGAS-STING inhibitors have entered clinical trials for AD. However, the future of AD treatment may involve modulation of neuroinflammatory pathways, with cGAS-STING inhibitors playing a central role in reshaping neuroimmune homeostasis.},
}

@article {pmid41481335,
year = {2026},
author = {Noreen, S and Nazir, R and Khan, M and Shah, SA},
title = {Schiff Base Complex rescues mice against scopolamine-induced cognitive dysfunction.},
journal = {Drug and chemical toxicology},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/01480545.2025.2606103},
pmid = {41481335},
issn = {1525-6014},
abstract = {Alzheimer's disease (AD) is a common and debilitating neurodegenerative disease characterized by progressive cognitive impairment, and oxidative stress is a recognized contributor. Despite numerous studies, effective treatments remain scarce. This study synthesized and assessed the neuroprotective effects of a Schiff base complex, Copper(II) 4-(benzylideneamino)-3-hydroxynaphthalene-1-sulfonic acid [Cu(BAHN)2], against scopolamine-induced (SCOP) cognitive and synaptic deficits in adult albino mice. Eight-week-old male BALB/c mice were randomly split into 4 groups: (1) controls (normal saline, 0.9%), (2) SCOP (1 mg/kg), (3) SCOP and Schiff base complex (30 mg/kg) and (4) Schiff base complex alone (30 mg/kg). Cognitive function was assessed using the Morris Water Maze (MWM) and Y-maze test. To assess the biochemical effects of the complex, antioxidant enzyme activities, and western blot analyses were performed. Treatment with the Schiff base complex significantly restored the activity of important antioxidant enzymes-catalase (CAT), peroxidase (POD), superoxide dismutase (SOD) and reduced glutathione (GSH) which were decreased by SCOP exposure. In addition, lipid peroxidation (LPO) rates were decreased. The complex also counteracted SCOP-induced decreases in both pre- and post-synaptic proteins, in line with improved behavioral performance in both cognitive challenges. Mechanistically, the compound activated phosphorylated Akt (p-Akt) and upregulated Nrf2 signaling, as well as downregulating nuclear factor kappa B (NF-kB) and interleukin-1β (IL-1β), show a decrease in neuroinflammation. In summary, these data suggest that the Schiff base complex reduces the oxidative, inflammatory, and synaptic deleterious effects of SCOP, probably, by regulating the p-Akt/Nrf2 pathway. Additional mechanistic studies are needed to understand its potential therapeutic implications in dementia.},
}

@article {pmid41481312,
year = {2026},
author = {Banik, A and Amaradhi, R and Sau, M and Rawat, V and Dingledine, R and Ganesh, T},
title = {Antagonism of the EP2 Receptor Reveals Sex-Specific Protection in a Two-Hit Mouse Model of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00780},
pmid = {41481312},
issn = {1948-7193},
abstract = {Neuroinflammation is evident in Alzheimer's disease (AD) brains, exacerbating the pathology and ensuing cognitive deficits in patients. The prostaglandin-E2 receptor EP2 emerged as a neuroinflammatory target in several neurodegenerative diseases, including AD. Antagonism of EP2 mitigates neuroinflammation and cognitive deficits in status epilepticus and stroke models. Here, we investigated the efficacy of a potent and selective EP2 antagonist TG11-77.HCl on the cognitive behavior and neuroinflammation in a two-hit 5xFAD mouse model of AD. We exposed adult 5xFAD mice on B6SJL genetic background and their nontransgenic littermates to a low dose of lipopolysaccharide and administered TG11-77.HCl or the vehicle in the drinking water for 12 weeks. Mice were subjected to Morris water maze and Y-maze testing during their last week of drug treatment. Blood samples were subjected to complete blood count (CBC) analysis and brain tissues were processed to examine the levels of inflammatory transcripts and glial marker expression (mRNA), followed by the quantification of congophilic amyloid deposition and microglial activation (IBA[+]) in the brain by immunohistochemistry. TG11-77.HCl treatment enhanced the spatial memory performance and ameliorated mRNA expression of proinflammatory mediators, chemokines, and cytokines in the neocortex of 5xFAD males only and attenuated astroglia and microglia activation in both male and female 5xFAD mice and the congophilic amyloid load in 5xFAD males only. CBC analysis revealed no changes in peripheral inflammation, irrespective of sex, on treatment with TG11-77.HCl. This study reveals sex-specific protection of selective EP2 antagonism in a two-hit mouse model of AD and supports a prudent therapeutic strategy against neuroinflammation and associated cognitive impairment in AD.},
}

@article {pmid41480618,
year = {2025},
author = {Hu, G and Gogzheyan, C and Panja, S and Sil, S and Gendelman, HE},
title = {Extracellular vesicle-based therapies for neurodegenerative diseases.},
journal = {NeuroImmune pharmacology and therapeutics},
volume = {4},
number = {4},
pages = {377-390},
pmid = {41480618},
issn = {2750-6665},
abstract = {Extracellular vesicles (EVs) are mediators of neurodegeneration and emerging therapeutic tools for central nervous system disorders. On the one hand, they help spread beta amyloid, tau, α-synuclein, TDP-43, and mutant SOD1, contributing to the signs and symptoms of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, and Huntington's Diseases. By activating glial cells, they promote chronic neuroinflammation through carrying cytokines, inflammasomes, and chemokines. On the other hand, EVs' ability to transport neuroregulatory products and cross the blood-brain barrier makes them ideal vehicles for drug delivery. Their function can be surface-modified to deliver targeted therapies, including anti-inflammatory and neuroprotective regulatory RNAs, proteins, and lipids, as well as factors that help maintain neural homeostasis. Notably, we suggest that colostrum-derived EVs, enriched with growth factors and immune-regulatory microRNAs, offer a natural, scalable, and biocompatible source for neuroprotective treatment. Although EVs can act as "Janus-faced" entities - serving both as disease initiators and versatile therapeutic vehicles - controlling their activity can enable immune-based therapeutics for neurodegenerative diseases.},
}

@article {pmid41480410,
year = {2026},
author = {Tang, S and Luo, W and Wu, S and Yuan, M and Wen, J and Zhong, G and Shen, L and Jiang, W and Cheng, C and Wu, X and Xiao, X},
title = {Hippocampus-targeted BDNF gene therapy to rescue cognitive impairments of Alzheimer's disease in multiple mouse models.},
journal = {Genes & diseases},
volume = {13},
number = {2},
pages = {101649},
pmid = {41480410},
issn = {2352-3042},
abstract = {Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of in vivo BDNF delivery requires further optimization, and the therapeutic efficacy of BDNF in AD animal models needs to be further evaluated. Here, we demonstrated that a newly engineered adeno-associated virus (AAV) serotype termed AAVT42 showed better tropism for neurons than AAV9 in the central nervous system (CNS). We analyzed the therapeutic potentials of AAVT42-delivered BDNF in three AD mouse models: amyloid precursor protein/presenilin-1 (APP/PS1), rTg4510, and 3 × Tg. Long-term BDNF expression in the hippocampus mitigated neuronal degeneration or loss in these AD mice, and alleviated their cognitive impairment, with no discernible effect on amyloid-β deposition or tau phosphorylation. Furthermore, transcriptomic analysis in 3 × Tg mice revealed that BDNF orchestrated the up-regulation of genes associated with neuronal structural organization and synaptic transmissions, such as Neuropeptide Y (Npy), Corticotropin-releasing hormone (Crh), Tachykinin precursor 1 (Tac1), and the down-regulation of Bone morphogenetic proteins (Bmps). Our study highlighted the efficacy of AAVT42 in gene delivery to CNS and validated the therapeutic benefits of BDNF in treating AD, which will be useful for future translational research on AD treatment using an AAV delivery system.},
}

@article {pmid41479956,
year = {2025},
author = {Massara, M and Vedovelli, L and Masina, F and M J Edelstyn, N and Silvia Bisiacchi, P and Di Rosa, E},
title = {From cigarettes to compulsions: a longitudinal study in de novo Parkinson's disease.},
journal = {Frontiers in psychology},
volume = {16},
number = {},
pages = {1708535},
pmid = {41479956},
issn = {1664-1078},
abstract = {INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Among the environmental and lifestyle factors associated with disease onset, cigarette smoking represents one of the most paradoxical. While substantial evidence has demonstrated a protective effect of smoking against the development of PD, smoking appears to worsen symptomatology, particularly by exacerbating impulsive-compulsive behaviors (ICBs) in people with PD (PwPD). However, longitudinal studies examining the effects of cigarette smoking on the progression of PD remain limited. Moreover, recent studies often involve mixed samples of treated and untreated PwPD, potentially confounding the impact of dopamine replacement therapy with that of smoking on ICBs.

METHODS: In the present study, we investigated a cohort of de novo PwPD, tracking their motor, cognitive, affective, and behavioral outcomes over 5 years, to better clarify the role of smoking in disease progression. Data were obtained from the Parkinson's Progression Markers Initiative and included 166 PwPD (119 non-smokers and 47 former smokers) and 79 healthy controls (48 non-smokers and 31 former smokers).

RESULTS: Our results revealed that a significantly higher percentage of former-smoker PwPD (28%) exhibited at least one ICB compared to non-smoker PwPD (13%; Pearson's [2](1) = 5.45, p = 0.02). No other significant differences between non-smokers and former smokers emerged in motor or non-motor symptoms, either in PwPD or in healthy individuals.

DISCUSSION: In conclusion, the novelty of our findings lies in showing that smoking-related influences on impulsive-compulsive behaviors in PD are most evident at the de novo stage, before any dopaminergic treatment. This temporal specificity may help resolve previous inconsistencies in the literature and underscores the importance of distinguishing between environmental and pharmacological effects on symptom development.},
}

@article {pmid41478829,
year = {2026},
author = {Meade, J and Mesa, H and Alamgir, S and Bieniecka, I and Liu, L and Zhang, Q},
title = {Synaptic toxicity of OGA inhibitors and the failure of ceperognastat.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100456},
doi = {10.1016/j.tjpad.2025.100456},
pmid = {41478829},
issn = {2426-0266},
abstract = {O-GlcNAcase inhibitors (OGAi) have emerged as a promising therapeutic strategy in Alzheimer's disease (AD) by enhancing O-GlcNAcylation, which competes with tau phosphorylation and reduces tau aggregation. However, the Phase II clinical trial failure of ceperognastat, marked by accelerated cognitive decline in the treatment group, has raised significant safety concerns. Here, we examined the acute synaptic effects of three structurally distinct OGAi compounds-ceperognastat, ASN90, and MK8719-in mouse hippocampal slices. Electrophysiological recordings revealed suppression of both short- and long-term synaptic plasticity, including paired-pulse facilitation/depression and long-term potentiation. Immunohistochemical analysis confirmed disrupted synaptic protein levels (increased PSD-95, reduced Synaptophysin 1) and a biphasic shift in tau phosphorylation. These convergent findings suggest a class-wide synaptotoxic mechanism and call for a great caution in the development of disease-modifying therapies in AD. We argue that preclinical drug screening for synaptic functionality is essential in CNS-targeted therapeutic pipelines.},
}

@article {pmid41478820,
year = {2026},
author = {Wang, P and Wu, X and Sun, F and Zhang, H and Jiang, Y and Wang, Q and Ding, H and Zhou, Y and Liu, F and Liu, H},
title = {Multi-omics integration reveals shared genetic architecture between metabolic markers and gray matter atrophy in Alzheimer's Disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100452},
doi = {10.1016/j.tjpad.2025.100452},
pmid = {41478820},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by widespread gray matter volume (GMV) reductions. Emerging evidence links glucose and lipid metabolic dysregulation to AD pathophysiology. However, the extent to which AD-related GMV alterations and metabolic traits share a common genetic basis remains poorly understood.

OBJECTIVES: To explore the shared genetic architecture between GMV alterations in AD and metabolites related to glucose and lipid metabolism, aiming to provide biological insights into the prevention and treatment of AD.

DESIGN: This is a multimodal, cross-disciplinary study combining neuroimaging meta-analysis, transcriptome-neuroimaging association analysis, conjunctional false discovery rate (conjFDR) analysis, and functional enrichment analysis to identify the shared genetic architecture between AD-related brain structural alterations and metabolic traits.

SETTING: Public databases and European populations.

PARTICIPANTS: The meta-analysis included 49 studies (1945 CE patients and 2598 controls). The largest genome-wide association study (GWAS) summary statistics were used for AD (Ncase = 39,918; Ncontrol =358,140), two glycemic traits-glucose (GLU, N = 459,772) and glycated hemoglobin (HbA1c, N = 146,864), and three lipid traits (N = 1320,016)-high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG).

MEASUREMENTS: We conducted a voxel-based morphometric meta-analysis of GMV in AD by systematically reviewing 49 neuroimaging studies, identified through a literature search in PubMed and Web of Science using a predefined search strategy. Building upon these neuroanatomical findings, we performed a transcriptome-neuroimaging association analysis using data from the Allen Human Brain Atlas to identify genes spatially correlated with GMV alterations. To further explore the shared genetic architecture, we integrated GWAS summary statistics for AD and five metabolic markers using conjFDR analysis. Finally, functional enrichment analyses were performed to elucidate the biological relevance of the identified genes through this integrative framework.

RESULTS: Consistent GMV reductions in AD were observed in the bilateral middle temporal gyrus, right superior temporal gyrus, and other key subcortical regions. The conjFDR analysis identified 20, 17, 78, 87, and 82 genes shared between AD-related GMV reductions and GLU, HbA1c, HDL-C, LDL-C, and TG, respectively. Notably, 6 genes were shared across all five metabolic markers. Enrichment analysis implicated these genes in biological processes related to Aβ aggregation and phosphatidylinositol metabolism.

CONCLUSIONS: This study reveals a convergent genetic architecture underlying AD-related GMV atrophy and metabolic dysfunction. These findings may offer novel insights into the molecular interplay between systemic metabolism and neurodegeneration in AD and highlight potential targets for therapeutic strategies.},
}

@article {pmid41478818,
year = {2026},
author = {Mummery, CJ and Li-Hsian, CC and Lasagna-Reeves, CA and Ossenkoppele, R and Rowe, CC and Scharre, DW and Wang, H and Kyaga, S and Cummings, JL},
title = {Tau in Alzheimer's disease: Shaping the future patient journey.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100447},
doi = {10.1016/j.tjpad.2025.100447},
pmid = {41478818},
issn = {2426-0266},
abstract = {Alzheimer's disease is a complex and multifactorial disease characterized by two key pathological hallmarks: amyloid-beta plaques and tau neurofibrillary tangles. Recent progress has led to the development and approval of disease-targeted therapies for Alzheimer's disease in the form of anti-amyloid-beta monoclonal antibodies. However, findings suggest that amelioration of multiple pathological drivers may be required to maximize clinical effect. An increasing body of evidence suggests that tau is a critical player in Alzheimer's disease pathophysiology, contributing significantly to neurodegeneration and cognitive decline. There are now several tau-targeting drugs in clinical development. In this review, we build on research and advancements in the field of tau to envision how an increasing focus on tau could shape the future Alzheimer's disease patient journey. We highlight the potential of tau as both a promising therapeutic target and a valuable biomarker, with the potential to inform treatment decisions and provide insight into disease trajectories. We also consider what a greater focus on tau may bring to an already evolving patient care pathway characterized by an increased influx of patients presenting earlier in the disease continuum, changes in workflow and infrastructural requirements, and increased complexity in treatment decision-making, treatment administration, treatment monitoring, and patient tracking. This review underscores the critical changes that may be required and knowledge gaps to be elucidated to ensure healthcare system preparedness for additional classes of disease-targeted therapy to move toward a next-generation, individualized treatment approach to Alzheimer's disease diagnosis and care.},
}

@article {pmid41478817,
year = {2026},
author = {Qi, L and Zheng, F and Tu, M and Abdullah, R and Zhao, Y and Su, X and Zhou, D and Peng, G},
title = {Safety profiles of lecanemab: A systematic review and meta-analysis of randomized controlled trials and real-world evidence.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100473},
doi = {10.1016/j.tjpad.2025.100473},
pmid = {41478817},
issn = {2426-0266},
abstract = {BACKGROUND: Safety profiles of lecanemab, an anti-amyloid-β antibody for the treatment of early Alzheimer's disease (AD), remain uncertain and may vary between randomized controlled trials (RCTs) and real-world evidence (RWE) studies.

OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the safety, tolerability, and acceptability of lecanemab based on findings from both RCTs and emerging RWE studies.

METHODS: We systematically searched major databases and clinical trial registries from their inception to June 2025. Random-effects meta-analyses were performed to estimate the pooled incidence of key safety outcomes, including amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation (due to ARIA, adverse events [AEs], or any cause). The risk of ARIA according to the ApoE4 genotype was assessed via relative risk (RR). This study was registered with PROSPERO (No. CRD420251110679).

RESULTS: A total of two RCTs and five RWE studies encompassing 1576 patients were included. The pooled ARIA incidence was 19% (95% CI: 16%-23%), which was significantly modulated by ApoE4 status (RR 1.45 for heterozygotes, 3.54 for homozygotes vs noncarriers) and the pooled symptomatic ARIA incidence was 3% (95% CI: 2%-4%). IRRs occurred in 26% (95% CI: 19%-34%), with heterogeneity reduced in patients receiving specific pre-infusion prophylaxis. The pooled rate of discontinuation due to AEs was 8% (95% CI: 5%-11%), with discontinuation due to ARIA occurring in 5% (95% CI: 3%-7%) of patients in RWE studies.

CONCLUSIONS: Lecanemab-related ARIA demonstrates a clear ApoE4 gene-dose effect, supporting routine ApoE4 genotyping before treatment. Standardizing pre-infusion prophylaxis may reduce variability in IRRs incidence, while prompt recognition and management of ARIA are critical for improving treatment tolerability. These findings provide important evidence to support the safe clinical use of lecanemab.},
}

@article {pmid41478541,
year = {2025},
author = {Zafar, I and Khan, MS and Jamal, A and Shafiq, S and Bahwerth, FS and Khan, NU},
title = {Precision therapeutic strategies for Alzheimer's disease: Amyloid β-targeted foundations and multimodal next-generation approaches.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104070},
doi = {10.1016/j.mcn.2025.104070},
pmid = {41478541},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and a significant unmet medical challenge, pathologically characterized by amyloid β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. Although Aβ has long been a central therapeutic target, clinical translation has historically been hindered by late-stage intervention, inadequate blood-brain barrier (BBB) penetration, and the molecular heterogeneity of AD. Recent advances with Aβ-targeted monoclonal antibodies, particularly lecanemab and donanemab, have provided the first clinical evidence of disease modification, demonstrating robust amyloid clearance and measurable slowing of cognitive decline in early-stage AD. These results validate the Aβ hypothesis but also highlight persistent barriers, including amyloid-related imaging abnormalities (ARIA), questions about the durability of benefit, challenges in patient stratification, and the high economic burden of biologics. To overcome these limitations, next-generation strategies are emerging that extend beyond single-pathway targeting toward multimodal and precision-based frameworks. Innovative approaches include tau-directed therapies to prevent the propagation of neurofibrillary tangles, immunomodulatory strategies to enhance microglial clearance of aggregated proteins, and neuroprotective interventions to counteract oxidative and inflammatory stress. Concurrently, nanotechnology-based drug delivery systems are being engineered to efficiently traverse the BBB and deliver multifunctional payloads, while artificial intelligence (AI)- driven discovery platforms are accelerating target identification, biomarker integration, and patient stratification. Future perspectives emphasize the importance of preclinical-stage intervention, long-term efficacy trials, and the adoption of personalised treatment paradigms that integrate genomic, biomarker, and digital profiling to optimise outcomes. Collectively, these advances signal a paradigm shift in AD therapeutics, positioning Aβ-targeted therapies as a foundation while paving the way for combination strategies that more effectively address the disease's multifactorial nature.},
}